['Cell-O', 'cycle-dependent-O', 'colocalization-O', 'of-O', 'BARD1-O', 'and-O', 'BRCA1-O', 'proteins-O', 'in-O', 'discrete-O', 'nuclear-O', 'domains.-O']
['Germ-line-O', 'mutations-O', 'of-O', 'the-O', 'BRCA1-O', 'gene-O', 'predispose-O', 'women-O', 'to-O', 'early-onset-O', 'breast-B-SpecificDisease', 'and-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'by-O', 'compromising-O', 'the-O', 'genes-O', 'presumptive-O', 'function-O', 'as-O', 'a-O', 'tumor-B-Modifier', 'suppressor.-O']
['Although-O', 'the-O', 'biochemical-O', 'properties-O', 'of-O', 'BRCA1-O', 'polypeptides-O', 'are-O', 'not-O', 'understood,-O', 'their-O', 'expression-O', 'pattern-O', 'and-O', 'subcellular-O', 'localization-O', 'suggest-O', 'a-O', 'role-O', 'in-O', 'cell-cycle-O', 'regulation.-O']
['When-O', 'resting-O', 'cells-O', 'are-O', 'induced-O', 'to-O', 'proliferate,-O', 'the-O', 'steady-state-O', 'levels-O', 'of-O', 'BRCA1-O', 'increase-O', 'in-O', 'late-O', 'G1-O', 'and-O', 'reach-O', 'a-O', 'maximum-O', 'during-O', 'S-O', 'phase.-O']
['Moreover,-O', 'in-O', 'S-O', 'phase-O', 'cells,-O', 'BRCA1-O', 'polypeptides-O', 'are-O', 'hyperphosphorylated-O', 'and-O', 'accumulate-O', 'into-O', 'discrete-O', 'subnuclear-O', 'foci-O', 'termed-O', '"-O', 'BRCA1-O', 'nuclear-O', 'dots.-O']
[',-O', 'BRCA1-O', 'associates-O', 'in-O', 'vivo-O', 'with-O', 'a-O', 'structurally-O', 'related-O', 'protein-O', 'termed-O', 'BARD1.-O']
['Here-O', 'we-O', 'show-O', 'that-O', 'the-O', 'steady-state-O', 'levels-O', 'of-O', 'BARD1,-O', 'unlike-O', 'those-O', 'of-O', 'BRCA1,-O', 'remain-O', 'relatively-O', 'constant-O', 'during-O', 'cell-O', 'cycle-O', 'progression.-O']
['However,-O', 'immunostaining-O', 'revealed-O', 'that-O', 'BARD1-O', 'resides-O', 'within-O', 'BRCA1-O', 'nuclear-O', 'dots-O', 'during-O', 'S-O', 'phase-O', 'of-O', 'the-O', 'cell-O', 'cycle,-O', 'but-O', 'not-O', 'during-O', 'the-O', 'G1-O', 'phase.-O']
['Nevertheless,-O', 'BARD1-O', 'polypeptides-O', 'are-O', 'found-O', 'exclusively-O', 'in-O', 'the-O', 'nuclear-O', 'fractions-O', 'of-O', 'both-O', 'G1-O', '-O', 'and-O', 'S-phase-O', 'cells.-O']
['Therefore,-O', 'progression-O', 'to-O', 'S-O', 'phase-O', 'is-O', 'accompanied-O', 'by-O', 'the-O', 'aggregation-O', 'of-O', 'nuclear-O', 'BARD1-O', 'polypeptides-O', 'into-O', 'BRCA1-O', 'nuclear-O', 'dots.-O']
['This-O', 'cell-O', 'cycle-dependent-O', 'colocalization-O', 'of-O', 'BARD1-O', 'and-O', 'BRCA1-O', 'indicates-O', 'a-O', 'role-O', 'for-O', 'BARD1-O', 'in-O', 'BRCA1-mediated-O', 'tumor-B-Modifier', 'suppression.-O']
['Eye-O', 'movement-O', 'abnormalities-O', 'correlate-O', 'with-O', 'genotype-O', 'in-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'cerebellar-B-Modifier', 'ataxia-I-Modifier', 'type-I-Modifier', 'I.-O', 'We-O', 'compared-O', 'horizontal-O', 'eye-O', 'movements-O', '(visually-O', 'guided-O', 'saccades,-O', 'antisaccades,-O', 'and-O', 'smooth-O', 'pursuit)-O', 'in-O', 'control-O', 'subjects-O', '(n-O', '=-O', '14)-O', 'and-O', 'patients-O', 'with-O', 'three-O', 'forms-O', 'of-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'cerebellar-B-Modifier', 'ataxias-O', 'type-I-Modifier', 'I-O', 'spinocerebellar-B-Modifier', 'ataxias-O', '1-O', 'and-O', '2-O', '(SCA1,-O', 'n-O', '=-O', '11;-O', 'SCA2,-O', 'n-O', '=-O', '10)-O', 'and-O', 'SCA3/Machado-Joseph-B-SpecificDisease', 'disease-I-SpecificDisease', '(MJD)-O', '(n-O', '=-O', '16).-O', 'In-O', 'SCA1,-O', 'saccade-O', 'amplitude-O', 'was-O', 'significantly-O', 'increased,-O', 'resulting-O', 'in-O', 'hypermetria.-O', 'The-O', 'smooth-O', 'pursuit-O', 'gain-O', 'was-O', 'decreased.-O']
['In-O', 'SCA2,-B-SpecificDisease', 'saccade-O', 'velocity-O', 'was-O', 'markedly-O', 'decreased.-O']
['The-O', 'percentage-O', 'of-O', 'errors-O', 'in-O', 'antisaccades-O', 'was-O', 'greatly-O', 'increased-O', 'and-O', 'was-O', 'significantly-O', 'correlated-O', 'with-O', 'age-O', 'at-O', 'disease-O', 'onset.-O']
['In-O', 'addition,-O', 'a-O', 'correlation-O', 'between-O', 'smooth-O', 'pursuit-O', 'gain-O', 'and-O', 'the-O', 'number-O', 'of-O', 'trinucleotide-O', 'repeats-O', 'was-O', 'found.-O']
['In-O', 'SCA3,-B-SpecificDisease', 'gaze-evoked-O', 'nystagmus-O', 'was-O', 'often-O', 'present-O', 'as-O', 'was-O', 'saccade-O', 'hypometria-O', 'and-O', 'smooth-O', 'pursuit-O', 'gain-O', 'was-O', 'markedly-O', 'decreased.-O']
['Three-O', 'major-O', 'criteria,-O', 'saccade-O', 'amplitude,-O', 'saccade-O', 'velocity,-O', 'and-O', 'presence-O', 'of-O', 'gaze-evoked-O', 'nystagmus,-O', 'permitted-O', 'the-O', 'correct-O', 'assignment-O', 'of-O', '90%-O', 'of-O', 'the-O', 'SCA1-B-SpecificDisease', ',O', '90%-O', 'of-O', 'the-O', 'SCA2-B-SpecificDisease', ',O', 'and-O', '93%-O', 'of-O', 'the-O', 'patients-O', 'with-O', 'SCA3-B-SpecificDisease', 'to-O', 'their-O', 'genetically-O', 'confirmed-O', 'patient-O', 'group-O', 'and,-O', 'therefore,-O', 'may-O', 'help-O', 'orient-O', 'diagnoses-O', 'of-O', 'SCA1-B-SpecificDisease', ',O', 'SCA2-B-SpecificDisease', ',O', 'and-O', 'SCA3-B-SpecificDisease', 'at-O', 'early-O', 'clinical-O', 'stages-O', 'of-O', 'the-O', 'diseases..-O']
['Diagnosis-O', 'of-O', 'hemochromatosis.-B-SpecificDisease', 'If-O', 'untreated,-O', 'hemochromatosis-I-SpecificDisease', 'can-O', 'cause-O', 'serious-O', 'illness-O', 'and-O', 'early-O', 'death,-O', 'but-O', 'the-O', 'disease-O', 'is-O', 'still-O', 'substantially-O', 'under-diagnosed.-O']
['The-O', 'cornerstone-O', 'of-O', 'screening-O', 'and-O', 'case-O', 'detection-O', 'is-O', 'the-O', 'measurement-O', 'of-O', 'serum-O', 'transferrin-O', 'saturation-O', 'and-O', 'the-O', 'serum-O', 'ferritin-O', 'level.-O']
['Once-O', 'the-O', 'diagnosis-O', 'is-O', 'suspected,-O', 'physicians-O', 'must-O', 'use-O', 'serum-O', 'ferritin-O', 'levels-O', 'and-O', 'hepatic-O', 'iron-O', 'stores-O', 'on-O', 'liver-O', 'biopsy-O', 'specimens-O', 'to-O', 'assess-O', 'patients-O', 'for-O', 'the-O', 'presence-O', 'of-O', 'iron-O', 'overload.-O', 'Liver-O', 'biopsy-O', 'is-O', 'also-O', 'used-O', 'to-O', 'establish-O', 'the-O', 'presence-O', 'or-O', 'absence-O', 'of-O', 'cirrhosis,-B-SpecificDisease', 'which-O', 'can-O', 'affect-O', 'prognosis-O', 'and-O', 'management.-O']
['A-O', 'DNA-based-O', 'test-O', 'for-O', 'the-O', 'HFE-B-SpecificDisease', 'gene-O', 'is-O', 'commercially-O', 'available,-O', 'but-O', 'its-O', 'place-O', 'in-O', 'the-O', 'diagnosis-O', 'of-O', 'hemochromatosis-B-Modifier', 'is-O', 'still-O', 'being-O', 'evaluated.-O']
['Currently,-O', 'the-O', 'most-O', 'useful-O', 'role-O', 'for-O', 'this-O', 'test-O', 'is-O', 'in-O', 'the-O', 'detection-O', 'of-O', 'hemochromatosis-B-Modifier', 'in-O', 'the-O', 'family-O', 'members-O', 'of-O', 'patients-O', 'with-O', 'a-O', 'proven-O', 'case-O', 'of-O', 'the-O', 'disease.-I-SpecificDisease']
['It-O', 'is-O', 'crucial-O', 'to-O', 'diagnose-O', 'hemochromatosis-B-SpecificDisease', 'before-O', 'hepatic-O', 'cirrhosis-I-SpecificDisease', 'develops-O', 'because-O', 'phlebotomy-O', 'therapy-O', 'can-O', 'avert-O', 'serious-O', 'chronic-O', 'disease-O', 'and-O', 'can-O', 'even-O', 'lead-O', 'to-O', 'normal-O', 'life-O', 'expectancy..-O']
['Low-O', 'levels-O', 'of-O', 'beta-O', 'hexosaminidase-O', 'A-O', 'in-O', 'healthy-O', 'individuals-O', 'with-O', 'apparent-O', 'deficiency-I-SpecificDisease', 'of-O', 'this-O', 'enzyme.-O']
['Appreciable-O', 'beta-O', 'hexosaminidase-O', 'A-O', '(hex-O', 'A)-O', 'activity-O', 'has-O', 'been-O', 'detected-O', 'in-O', 'cultured-O', 'skin-O', 'fibroblasts-O', 'and-O', 'melanoma-O', 'tissue-O', 'from-O', 'healthy-O', 'individuals-O', 'previously-O', 'reported-O', 'as-O', 'having-O', 'deficiency-O', 'of-O', 'hex-O', 'A-O', 'activity-O', 'indistinguishable-O', 'from-O', 'that-O', 'of-O', 'patients-O', 'with-O', 'Tay-Sachs-B-SpecificDisease', 'disease-I-SpecificDisease', '(TSD).-O', 'Identification-O', 'and-O', 'quantitation-O', 'of-O', 'hex-O', 'A,-O', 'amounting-O', 'to-O', '3.-O']
['5%-O', '-6.-O']
['9%-O', 'of-O', 'total-O', 'beta-O', 'hexosaminidase-O', 'activity,-O', 'has-O', 'been-O', 'obtained-O', 'by-O', 'cellulose-O', 'acetate-O', 'gel-O', 'electrophoresis,-O', 'DEAE-cellulose-O', 'ion-exchange-O', 'chromatography,-O', 'radial-O', 'immunodiffusion,-O', 'and-O', 'radioimmunoassay.-O']
['Previous-O', 'family-O', 'studies-O', 'suggested-O', 'that-O', 'these-O', 'individuals-O', 'may-O', 'be-O', 'compound-O', 'heterozygotes-O', 'for-O', 'the-O', 'common-O', 'mutant-O', 'TSD-B-Modifier', 'gene-O', 'and-O', 'a-O', 'rare-O', '(allelic)-O', 'mutant-O', 'gene.-O']
['Thus,-O', 'the-O', 'postulated-O', 'rate-O', 'mutant-O', 'gene-O', 'appears-O', 'to-O', 'code-O', 'for-O', 'the-O', 'expression-O', 'of-O', 'low-O', 'amounts-O', 'of-O', 'hex-O', 'A.-O']
['Heterozygotes-O', 'for-O', 'the-O', 'rare-O', 'mutant-O', 'may-O', 'be-O', 'indistinguishable-O', 'from-O', 'heterozygotes-O', 'for-O', 'the-O', 'common-O', 'TSD-B-Modifier', 'mutant.-O']
['However,-O', 'direct-O', 'visualization-O', 'and-O', 'quantitation-O', 'of-O', 'hex-O', 'A-O', 'by-O', 'the-O', 'methods-O', 'described-O', 'may-O', 'prevent-O', 'false-positive-O', 'prenatal-O', 'diagnosis-O', 'of-O', 'TSD-B-SpecificDisease', 'in-O', 'fetuses-O', 'having-O', 'the-O', 'incomplete-O', 'hex-O', 'A-O', 'deficiency-O', 'of-O', 'the-O', 'type-O', 'described-O', 'in-O', 'the-O', 'four-O', 'healthy-O', 'individuals.-O']
['Piebaldism-B-SpecificDisease', 'with-O', 'deafness:-B-SpecificDisease', 'molecular-O', 'evidence-O', 'for-O', 'an-O', 'expanded-O', 'syndrome.-I-SpecificDisease']
['In-O', 'a-O', 'South-O', 'African-O', 'girl-O', 'of-O', 'Xhosa-O', 'stock-O', 'with-O', 'severe-O', 'piebaldism-B-SpecificDisease', 'and-O', 'profound-O', 'congenital-B-SpecificDisease', 'sensorineural-I-SpecificDisease', 'deafness-I-SpecificDisease', 'we-O', 'identified-O', 'a-O', 'novel-O', 'missense-O', 'substitution-O', 'at-O', 'a-O', 'highly-O', 'conserved-O', 'residue-O', 'in-O', 'the-O', 'intracellular-O', 'kinase-O', 'domain-O', 'of-O', 'the-O', 'KIT-B-Modifier', 'proto-oncogene,-O', 'R796G.-O']
['Though-O', 'auditory-O', 'anomalies-O', 'have-O', 'been-O', 'observed-O', 'in-O', 'mice-O', 'with-O', 'dominant-O', 'white-O', 'spotting-O', '(W)-O', 'due-O', 'to-O', 'KIT-O', 'mutations,-O', 'deafness-O', 'is-O', 'not-O', 'typical-O', 'in-O', 'human-O', 'piebaldism.-B-SpecificDisease', 'Thus,-O', 'the-O', 'occurrence-O', 'of-O', 'sensorineural-O', 'deafness-B-SpecificDisease', 'in-O', 'this-O', 'patient-O', 'extends-O', 'considerably-O', 'the-O', 'phenotypic-O', 'range-O', 'of-O', 'piebaldism-B-SpecificDisease', 'due-O', 'to-O', 'KIT-O', 'gene-O', 'mutation-O', 'in-O', 'humans-O', 'and-O', 'tightens-O', 'the-O', 'clinical-O', 'similarity-O', 'between-O', 'piebaldism-B-SpecificDisease', 'and-O', 'the-O', 'various-O', 'forms-O', 'of-O', 'Waardenburg-B-SpecificDisease', 'syndrome..-I-SpecificDisease']
['W474C-O', 'amino-O', 'acid-O', 'substitution-O', 'affects-O', 'early-O', 'processing-O', 'of-O', 'the-O', 'alpha-subunit-O', 'of-O', 'beta-hexosaminidase-O', 'A-O', 'and-O', 'is-O', 'associated-O', 'with-O', 'subacute-O', 'G(M2)-I-SpecificDisease', 'gangliosidosis.-I-SpecificDisease', 'Mutations-O', 'in-O', 'the-O', 'HEXA-O', 'gene,-O', 'encoding-O', 'the-O', 'alpha-subunit-O', 'of-O', 'beta-hexosaminidase-O', 'A-O', '(Hex-O', 'A),-O', 'that-O', 'abolish-O', 'Hex-O', 'A-O', 'enzyme-O', 'activity-O', 'cause-O', 'Tay-Sachs-B-SpecificDisease', 'disease-I-SpecificDisease', '(TSD),-O', 'the-O', 'fatal-O', 'infantile-O', 'form-O', 'of-O', 'G-O', '(M2)-I-SpecificDisease', 'gangliosidosis,-I-SpecificDisease', 'Type-O', '1.-O', 'Less-O', 'severe,-O', 'subacute-O', '(juvenile-onset)-O', 'and-O', 'chronic-O', '(adult-onset)-O', 'variants-O', 'are-O', 'characterized-O', 'by-O', 'a-O', 'broad-O', 'spectrum-O', 'of-O', 'clinical-O', 'manifestations-O', 'and-O', 'are-O', 'associated-O', 'with-O', 'residual-O', 'levels-O', 'of-O', 'Hex-O', 'A-O', 'enzyme-O', 'activity.-O']
['We-O', 'identified-O', 'a-O', '1422-O', 'G--O', '>', 'C-O', '(amino-O', 'acid-O', 'W474C)-O', 'substitution-O', 'in-O', 'the-O', 'first-O', 'position-O', 'of-O', 'exon-O', '13-O', 'of-O', 'HEXA-O', 'of-O', 'a-O', 'non-Jewish-O', 'proband-O', 'who-O', 'manifested-O', 'a-O', 'subacute-O', 'variant-O', 'of-O', 'G-O', '(M2)-O', 'gangliosidosis.-B-SpecificDisease', 'On-O', 'the-O', 'second-O', 'maternally-O', 'inherited-O', 'allele,-O', 'we-O', 'identified-O', 'the-O', 'common-O', 'infantile-O', 'disease-causing-O', '4-bp-O', 'insertion,-O', '+-O', 'TATC-O', '1278,-O', 'in-O', 'exon-O', '11.-O']
['Pulse-chase-O', 'analysis-O', 'using-O', 'proband-O', 'fibroblasts-O', 'revealed-O', 'that-O', 'the-O', 'W474C-containing-O', 'alpha-subunit-O', 'precursor-O', 'was-O', 'normally-O', 'synthesized,-O', 'but-O', 'not-O', 'phosphorylated-O', 'or-O', 'secreted,-O', 'and-O', 'the-O', 'mature-O', 'lysosomal-O', 'alpha-subunit-O', 'was-O', 'not-O', 'detected.-O']
['When-O', 'the-O', 'W474C-containing-O', 'alpha-subunit-O', 'was-O', 'transiently-O', 'co-expressed-O', 'with-O', 'the-O', 'beta-subunit-O', 'to-O', 'produce-O', 'Hex-O', 'A-O', '(alphabeta)-O', 'in-O', 'COS-7-O', 'cells,-O', 'the-O', 'mature-O', 'alpha-subunit-O', 'was-O', 'present,-O', 'but-O', 'its-O', 'level-O', 'was-O', 'much-O', 'lower-O', 'than-O', 'that-O', 'from-O', 'normal-O', 'alpha-subunit-O', 'transfections,-O', 'although-O', 'higher-O', 'than-O', 'in-O', 'those-O', 'cells-O', 'transfected-O', 'with-O', 'an-O', 'alpha-subunit-O', 'associated-O', 'with-O', 'infantile-B-SpecificDisease', 'TSD.-I-SpecificDisease', 'Furthermore,-O', 'the-O', 'precursor-O', 'level-O', 'of-O', 'the-O', 'W474C-O', 'alpha-subunit-O', 'was-O', 'found-O', 'to-O', 'accumulate-O', 'in-O', 'comparison-O', 'to-O', 'the-O', 'normal-O', 'alpha-subunit-O', 'precursor-O', 'levels.-O']
['We-O', 'conclude-O', 'that-O', 'the-O', '1422-O', 'G--O', '>', 'C-O', 'mutation-O', 'is-O', 'the-O', 'cause-O', 'of-O', 'Hex-B-SpecificDisease', 'A-I-SpecificDisease', 'enzyme-I-SpecificDisease', 'deficiency-I-SpecificDisease', 'in-O', 'the-O', 'proband.-O']
['The-O', 'resulting-O', 'W474C-O', 'substitution-O', 'clearly-O', 'interferes-O', 'with-O', 'alpha-subunit-O', 'processing,-O', 'but-O', 'because-O', 'the-O', 'base-O', 'substitution-O', 'falls-O', 'at-O', 'the-O', 'first-O', 'position-O', 'of-O', 'exon-O', '13,-O', 'aberrant-O', 'splicing-O', 'may-O', 'also-O', 'contribute-O', 'to-O', 'Hex-O', 'A-O', 'deficiency-O', 'in-O', 'this-O', 'proband..-O']
['The-O', 'hemochromatosis-B-Modifier', 'gene-O', 'product-O', 'complexes-O', 'with-O', 'the-O', 'transferrin-O', 'receptor-O', 'and-O', 'lowers-O', 'its-O', 'affinity-O', 'for-O', 'ligand-O', 'binding.-O']
['We-O', 'recently-O', 'reported-O', 'the-O', 'positional-O', 'cloning-O', 'of-O', 'a-O', 'candidate-O', 'gene-O', 'for-O', 'hereditary-B-SpecificDisease', 'hemochromatosis-I-SpecificDisease', 'called-O', 'HFE.-O']
['The-O', 'gene-O', 'product,-O', 'a-O', 'member-O', 'of-O', 'the-O', 'major-O', 'histocompatibility-O', 'complex-O', 'class-O', 'I-like-O', 'family,-O', 'was-O', 'found-O', 'to-O', 'have-O', 'a-O', 'mutation,-O', 'Cys-282-O', '--', '>O', 'Tyr-O', '(C282Y),-O', 'in-O', '85%-O', 'of-O', 'patient-O', 'chromosomes.-O']
['This-O', 'mutation-O', 'eliminates-O', 'the-O', 'ability-O', 'of-O', 'HFE-O', 'to-O', 'associate-O', 'with-O', 'beta2-microglobulin-O', '(beta2m)-O', 'and-O', 'prevents-O', 'cell-surface-O', 'expression.-O']
['A-O', 'second-O', 'mutation-O', 'that-O', 'has-O', 'no-O', 'effect-O', 'on-O', 'beta2m-O', 'association,-O', 'H63D,-O', 'was-O', 'found-O', 'in-O', 'eight-O', 'out-O', 'of-O', 'nine-O', 'patients-O', 'heterozygous-O', 'for-O', 'the-O', 'C282Y-O', 'mutant.-O']
['In-O', 'this-O', 'report,-O', 'we-O', 'demonstrate-O', 'in-O', 'cultured-O', '293-O', 'cells-O', 'overexpressing-O', 'wild-type-O', 'or-O', 'mutant-O', 'HFE-O', 'proteins-O', 'that-O', 'both-O', 'the-O', 'wild-type-O', 'and-O', 'H63D-O', 'HFE-O', 'proteins-O', 'form-O', 'stable-O', 'complexes-O', 'with-O', 'the-O', 'transferrin-O', 'receptor-O', '(TfR).-O', 'The-O', 'C282Y-O', 'mutation-O', 'nearly-O', 'completely-O', 'prevents-O', 'the-O', 'association-O', 'of-O', 'the-O', 'mutant-O', 'HFE-O', 'protein-O', 'with-O', 'the-O', 'TfR.-O']
['Studies-O', 'on-O', 'cell-associated-O', 'transferrin-O', 'at-O', '37-O', 'degrees-O', 'C-O', 'suggest-O', 'that-O', 'the-O', 'overexpressed-O', 'wild-type-O', 'HFE-O', 'protein-O', 'decreases-O', 'the-O', 'affinity-O', 'of-O', 'the-O', 'TfR-O', 'for-O', 'transferrin.-O']
['The-O', 'overexpressed-O', 'H63D-O', 'protein-O', 'does-O', 'not-O', 'have-O', 'this-O', 'effect,-O', 'providing-O', 'the-O', 'first-O', 'direct-O', 'evidence-O', 'for-O', 'a-O', 'functional-O', 'consequence-O', 'of-O', 'the-O', 'H63D-O', 'mutation.-O']
['Addition-O', 'of-O', 'soluble-O', 'wild-type-O', 'HFE-O', '/beta2m-O', 'heterodimers-O', 'to-O', 'cultured-O', 'cells-O', 'also-O', 'decreased-O', 'the-O', 'apparent-O', 'affinity-O', 'of-O', 'the-O', 'TfR-O', 'for-O', 'its-O', 'ligand-O', 'under-O', 'steady-state-O', 'conditions,-O', 'both-O', 'in-O', '293-O', 'cells-O', 'and-O', 'in-O', 'HeLa-O', 'cells.-O']
['Furthermore,-O', 'at-O', '4-O', 'degrees-O', 'C,-O', 'the-O', 'added-O', 'soluble-O', 'complex-O', 'of-O', 'HFE-B-Modifier', '/beta2m-O', 'inhibited-O', 'binding-O', 'of-O', 'transferrin-O', 'to-O', 'HeLa-O', 'cell-O', 'TfR-O', 'in-O', 'a-O', 'concentration-dependent-O', 'manner.-O']
['Scatchard-O', 'plots-O', 'of-O', 'these-O', 'data-O', 'indicate-O', 'that-O', 'the-O', 'added-O', 'heterodimer-O', 'substantially-O', 'reduced-O', 'the-O', 'affinity-O', 'of-O', 'TfR-O', 'for-O', 'transferrin.-O']
['These-O', 'results-O', 'establish-O', 'a-O', 'molecular-O', 'link-O', 'between-O', 'HFE-O', 'and-O', 'a-O', 'key-O', 'protein-O', 'involved-O', 'in-O', 'iron-O', 'transport,-O', 'the-O', 'TfR,-O', 'and-O', 'raise-O', 'the-O', 'possibility-O', 'that-O', 'alterations-O', 'in-O', 'this-O', 'regulatory-O', 'mechanism-O', 'may-O', 'play-O', 'a-O', 'role-O', 'in-O', 'the-O', 'pathogenesis-O', 'of-O', 'hereditary-B-SpecificDisease', 'hemochromatosis..-I-SpecificDisease']
['A-O', 'European-O', 'multicenter-O', 'study-O', 'of-O', 'phenylalanine-O', 'hydroxylase-O', 'deficiency:-B-SpecificDisease', 'classification-O', 'of-O', '105-O', 'mutations-O', 'and-O', 'a-O', 'general-O', 'system-O', 'for-O', 'genotype-based-O', 'prediction-O', 'of-O', 'metabolic-O', 'phenotype.-O']
['Phenylketonuria-B-SpecificDisease', '(PKU)-O', 'and-O', 'mild-B-SpecificDisease', 'hyperphenylalaninemia-I-SpecificDisease', '(MHP)-O', 'are-O', 'allelic-O', 'disorders-O', 'caused-O', 'by-O', 'mutations-O', 'in-O', 'the-O', 'gene-O', 'encoding-O', 'phenylalanine-O', 'hydroxylase-O', '(PAH)-O', 'Previous-O', 'studies-O', 'have-O', 'suggested-O', 'that-O', 'the-O', 'highly-O', 'variable-O', 'metabolic-O', 'phenotypes-O', 'of-O', 'PAH-O', 'deficiency-O', 'correlate-O', 'with-O', 'PAH-O', 'genotypes.-O']
['We-O', 'identified-O', 'both-O', 'causative-O', 'mutations-O', 'in-O', '686-O', 'patients-O', 'from-O', 'seven-O', 'European-O', 'centers.-O']
['On-O', 'the-O', 'basis-O', 'of-O', 'the-O', 'phenotypic-O', 'characteristics-O', 'of-O', '297-O', 'functionally-O', 'hemizygous-O', 'patients,-O', '105-O', 'of-O', 'the-O', 'mutations-O', 'were-O', 'assigned-O', 'to-O', 'one-O', 'of-O', 'four-O', 'arbitrary-O', 'phenotype-O', 'categories.-O']
['We-O', 'proposed-O', 'and-O', 'tested-O', 'a-O', 'simple-O', 'model-O', 'for-O', 'correlation-O', 'between-O', 'genotype-O', 'and-O', 'phenotypic-O', 'outcome.-O']
['The-O', 'observed-O', 'phenotype-O', 'matched-O', 'the-O', 'predicted-O', 'phenotype-O', 'in-O', '79%-O', 'of-O', 'the-O', 'cases,-O', 'and-O', 'in-O', 'only-O', '5-O', 'of-O', '184-O', 'patients-O', 'was-O', 'the-O', 'observed-O', 'phenotype-O', 'more-O', 'than-O', 'one-O', 'category-O', 'away-O', 'from-O', 'that-O', 'expected.-O']
['Among-O', 'the-O', 'seven-O', 'contributing-O', 'centers,-O', 'the-O', 'proportion-O', 'of-O', 'patients-O', 'for-O', 'whom-O', 'the-O', 'observed-O', 'phenotype-O', 'did-O', 'not-O', 'match-O', 'the-O', 'predicted-O', 'phenotype-O', 'was-O', '4%-O', '-23%-O', '(P-O', '<.-O', '0001),-O', 'suggesting-O', 'that-O', 'differences-O', 'in-O', 'methods-O', 'used-O', 'for-O', 'mutation-O', 'detection-O', 'or-O', 'phenotype-O', 'classification-O', 'may-O', 'account-O', 'for-O', 'a-O', 'considerable-O', 'proportion-O', 'of-O', 'genotype-phenotype-O', 'inconsistencies.-O']
['Our-O', 'data-O', 'indicate-O', 'that-O', 'the-O', 'PAH-mutation-O', 'genotype-O', 'is-O', 'the-O', 'main-O', 'determinant-O', 'of-O', 'metabolic-O', 'phenotype-O', 'in-O', 'most-O', 'patients-O', 'with-O', 'PAH-B-SpecificDisease', 'deficiency.-I-SpecificDisease', 'In-O', 'the-O', 'present-O', 'study,-O', 'the-O', 'classification-O', 'of-O', '105-O', 'PAH-O', 'mutations-O', 'may-O', 'allow-O', 'the-O', 'prediction-O', 'of-O', 'the-O', 'biochemical-O', 'phenotype-O', 'in-O', '>10,-O', '000-O', 'genotypes,-O', 'which-O', 'may-O', 'be-O', 'useful-O', 'for-O', 'the-O', 'management-O', 'of-O', 'hyperphenylalaninemia-B-Modifier', 'in-O', 'newborns.-O']
['The-O', 'RB1-O', 'gene-O', 'mutation-O', 'in-O', 'a-O', 'child-O', 'with-O', 'ectopic-O', 'intracranial-O', 'retinoblastoma.-B-SpecificDisease', 'The-O', 'RB1-O', 'gene-O', 'mutation-O', 'was-O', 'investigated-O', 'in-O', 'a-O', 'child-O', 'with-O', 'ectopic-O', 'intracranial-O', 'retinoblastoma.-B-SpecificDisease', 'using-O', 'DNA-O', 'obtained-O', 'from-O', 'both-O', 'the-O', 'pineal-O', 'and-O', 'retinal-O', 'tumours-O', 'of-O', 'the-O', 'patient.-O']
['A-O', 'nonsense-O', 'mutation-O', 'in-O', 'exon-O', '17-O', '(codon-O', '556)-O', 'of-O', 'the-O', 'RB1-O', 'gene-O', 'was-O', 'found-O', 'to-O', 'be-O', 'present-O', 'homozygously-O', 'in-O', 'both-O', 'the-O', 'retinal-O', 'and-O', 'the-O', 'pineal-O', 'tumours.-I-DiseaseClass', 'The-O', 'same-O', 'mutation-O', 'was-O', 'present-O', 'heterozygously-O', 'in-O', 'the-O', 'DNA-O', 'from-O', 'the-O', 'constitutional-O', 'cells-O', 'of-O', 'the-O', 'patient,-O', 'proving-O', 'it-O', 'to-O', 'be-O', 'of-O', 'germline-O', 'origin.-O']
['The-O', 'initial-O', 'mutation-O', 'was-O', 'shown-O', 'to-O', 'have-O', 'occurred-O', 'in-O', 'the-O', 'paternally-O', 'derived-O', 'RB1-O', 'allele.-O']
['The-O', 'mutation-O', 'is-O', 'in-O', 'an-O', 'area-O', 'of-O', 'the-O', 'gene-O', 'that-O', 'encodes-O', 'the-O', 'protein-binding-O', 'region-O', 'known-O', 'as-O', 'the-O', 'pocket-O', 'region-O', 'and-O', 'has-O', 'been-O', 'detected-O', 'in-O', 'other-O', 'cases-O', 'of-O', 'retinoblastoma.-B-SpecificDisease']
['Myotonic-B-Modifier', 'dystrophy-I-Modifier', 'protein-O', 'kinase-O', 'is-O', 'involved-O', 'in-O', 'the-O', 'modulation-O', 'of-O', 'the-O', 'Ca2+-O', 'homeostasis-O', 'in-O', 'skeletal-O', 'muscle-O', 'cells.-O']
['Myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM),-O', 'the-O', 'most-O', 'prevalent-O', 'muscular-B-DiseaseClass', 'disorder-I-DiseaseClass', 'in-O', 'adults,-O', 'is-O', 'caused-O', 'by-O', '(CTG)-O', 'n-repeat-O', 'expansion-O', 'in-O', 'a-O', 'gene-O', 'encoding-O', 'a-O', 'protein-O', 'kinase-O', '(DM-O', 'protein-O', 'kinase;-O', 'DMPK)-O', 'and-O', 'involves-O', 'changes-O', 'in-O', 'cytoarchitecture-O', 'and-O', 'ion-O', 'homeostasis.-O']
['To-O', 'obtain-O', 'clues-O', 'to-O', 'the-O', 'normal-O', 'biological-O', 'role-O', 'of-O', 'DMPK-O', 'in-O', 'cellular-O', 'ion-O', 'homeostasis,-O', 'we-O', 'have-O', 'compared-O', 'the-O', 'resting-O', '[Ca2-O', '+]-O', 'i,-O', 'the-O', 'amplitude-O', 'and-O', 'shape-O', 'of-O', 'depolarization-induced-O', 'Ca2-O', '+-O', 'transients,-O', 'and-O', 'the-O', 'content-O', 'of-O', 'ATP-driven-O', 'ion-O', 'pumps-O', 'in-O', 'cultured-O', 'skeletal-O', 'muscle-O', 'cells-O', 'of-O', 'wild-type-O', 'and-O', 'DMPK-O', '[-/-]-O', 'knockout-O', 'mice.-O']
['In-O', 'vitro-differentiated-O', 'DMPK-O', '[-/-]-O', 'myotubes-O', 'exhibit-O', 'a-O', 'higher-O', 'resting-O', '[Ca2-O', '+]-O', 'i-O', 'than-O', 'do-O', 'wild-type-O', 'myotubes-O', 'because-O', 'of-O', 'an-O', 'altered-O', 'open-O', 'probability-O', 'of-O', 'voltage-dependent-O', 'l-type-O', 'Ca2-O', '+-O', 'and-O', 'Na-O', '+-O', 'channels.-O']
['The-O', 'mutant-O', 'myotubes-O', 'exhibit-O', 'smaller-O', 'and-O', 'slower-O', 'Ca2+-O', 'responses-O', 'upon-O', 'triggering-O', 'by-O', 'acetylcholine-O', 'or-O', 'high-O', 'external-O', 'K+-O', '.', 'In-O', 'addition,-O', 'we-O', 'observed-O', 'that-O', 'these-O', 'Ca2+-O', 'transients-O', 'partially-O', 'result-O', 'from-O', 'an-O', 'influx-O', 'of-O', 'extracellular-O', 'Ca2+-O', 'through-O', 'the-O', 'l-type-O', 'Ca2+-O', 'channel.-O']
['Neither-O', 'the-O', 'content-O', 'nor-O', 'the-O', 'activity-O', 'of-O', 'Na-O', '+/K-O', '+-O', 'ATPase-O', 'and-O', 'sarcoplasmic-O', 'reticulum-O', 'Ca2-O', '+-O', '-ATPase-O', 'are-O', 'affected-O', 'by-O', 'DMPK-B-Modifier', 'absence.-O']
['In-O', 'conclusion,-O', 'our-O', 'data-O', 'suggest-O', 'that-O', 'DMPK-O', 'is-O', 'involved-O', 'in-O', 'modulating-O', 'the-O', 'initial-O', 'events-O', 'of-O', 'excitation-contraction-O', 'coupling-O', 'in-O', 'skeletal-O', 'muscle..-O']
['The-O', '185delAG-O', 'BRCA1-O', 'mutation-O', 'originated-O', 'before-O', 'the-O', 'dispersion-O', 'of-O', 'Jews-O', 'in-O', 'the-O', 'diaspora-O', 'and-O', 'is-O', 'not-O', 'limited-O', 'to-O', 'Ashkenazim.-O']
['The-O', '185delAG-O', 'mutation-O', 'in-O', 'BRCA1-O', 'is-O', 'detected-O', 'in-O', 'Ashkenazi-O', 'Jews-O', 'both-O', 'in-O', 'familial-B-SpecificDisease', 'breast-I-SpecificDisease', 'and-I-SpecificDisease', 'ovarian-I-SpecificDisease', 'cancer-I-SpecificDisease', 'and-O', 'in-O', 'the-O', 'general-O', 'population.-O']
['All-O', 'tested-O', 'Ashkenazi-O', 'mutation-O', 'carriers-O', 'share-O', 'the-O', 'same-O', 'allelic-O', 'pattern-O', 'at-O', 'the-O', 'BRCA1-O', 'locus.-O']
['Our-O', 'previous-O', 'study-O', 'showed-O', 'that-O', 'this-O', 'Ashkenazi-O', 'mutation-O', 'also-O', 'occurs-O', 'in-O', 'Iraqi-O', 'Jews-O', 'with-O', 'a-O', 'similar-O', 'allelic-O', 'pattern.-O']
['We-O', 'extended-O', 'our-O', 'analysis-O', 'to-O', 'other-O', 'non-Ashkenazi-O', 'subsets-O', '354-O', 'of-O', 'Moroccan-O', 'origin,-O', '200-O', 'Yemenites-O', 'and-O', '150-O', 'Iranian-O', 'Jews.-O']
['Heteroduplex-O', 'analysis-O', 'complemented-O', 'by-O', 'direct-O', 'DNA-O', 'sequencing-O', 'of-O', 'abnormally-O', 'migrating-O', 'bands-O', 'were-O', 'employed.-O']
['Four-O', 'of-O', 'Moroccan-O', 'origin-O', '(1.-O']
['1%)-O', 'and-O', 'none-O', 'of-O', 'the-O', 'Yemenites-O', 'or-O', 'Iranians-O', 'was-O', 'a-O', 'carrier-O', 'of-O', 'the-O', '185delAG-O', 'mutation.-O']
['BRCA1-O', 'allelic-O', 'patterns-O', 'were-O', 'determined-O', 'for-O', 'four-O', 'of-O', 'these-O', 'individuals-O', 'and-O', 'for-O', '12-O', 'additional-O', 'non-Ashkenazi-O', '185delAG-O', 'mutation-O', 'carriers-O', 'who-O', 'had-O', 'breast/ovarian-B-Modifier', 'cancer.-I-Modifier', 'Six-O', 'non-Ashkenazi-O', 'individuals-O', 'shared-O', 'the-O', 'common-O', 'Ashkenazi-O', 'haplotype,-O', 'four-O', 'had-O', 'a-O', 'closely-O', 'related-O', 'pattern,-O', 'and-O', 'the-O', 'rest-O', '(n-O', '=', '6)-O', 'displayed-O', 'a-O', 'distinct-O', 'BRCA1-O', 'allelic-O', 'pattern.-O']
['We-O', 'conclude-O', 'that-O', 'the-O', '185delAG-O', 'BRCA1-O', 'mutation-O', 'occurs-O', 'in-O', 'some-O', 'non-Ashkenazi-O', 'populations-O', 'at-O', 'rates-O', 'comparable-O', 'with-O', 'that-O', 'of-O', 'Ashkenazim.-O']
['The-O', 'majority-O', 'of-O', 'Jewish-O', '185delAG-O', 'mutation-O', 'carriers-O', 'have-O', 'a-O', 'common-O', 'allelic-O', 'pattern,-O', 'supporting-O', 'the-O', 'founder-O', 'effect-O', 'notion,-O', 'but-O', 'dating-O', 'the-O', 'mutations-O', 'origin-O', 'to-O', 'an-O', 'earlier-O', 'date-O', 'than-O', 'currently-O', 'estimated.-O']
['However,-O', 'the-O', 'different-O', 'allelic-O', 'pattern-O', 'at-O', 'the-O', 'BRCA1-O', 'locus-O', 'even-O', 'in-O', 'some-O', 'Jewish-O', 'mutation-O', 'carriers,-O', 'might-O', 'suggest-O', 'that-O', 'the-O', 'mutation-O', 'arose-O', 'independently..-O']
['Oral-O', 'contraceptives-O', 'and-O', 'the-O', 'risk-O', 'of-O', 'hereditary-B-Modifier', 'ovarian-I-Modifier', 'cancer.-I-Modifier', 'Hereditary-B-DiseaseClass', 'Ovarian-I-DiseaseClass', 'Cancer-I-DiseaseClass', 'Clinical-O', 'Study-O', 'Group.-O']
['BACKGROUND-O', 'Women-O', 'with-O', 'mutations-O', 'in-O', 'either-O', 'the-O', 'BRCA1-O', 'or-O', 'the-O', 'BRCA2-O', 'gene-O', 'have-O', 'a-O', 'high-O', 'lifetime-O', 'risk-O', 'of-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease.', 'Oral-O', 'contraceptives-O', 'protect-O', 'against-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'in-O', 'general,-O', 'but-O', 'it-O', 'is-O', 'not-O', 'known-O', 'whether-O', 'they-O', 'also-O', 'protect-O', 'against-O', 'hereditary-B-Modifier', 'forms-O', 'of-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease.', 'METHODS-O', 'We-O', 'enrolled-O', '207-O', 'women-O', 'with-O', 'hereditary-B-Modifier', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'and-O', '161-O', 'of-O', 'their-O', 'sisters-O', 'as-O', 'controls-O', 'in-O', 'a-O', 'case-control-O', 'study.-O']
['All-O', 'the-O', 'patients-O', 'carried-O', 'a-O', 'pathogenic-O', 'mutation-O', 'in-O', 'either-O', 'BRCA1-O', '(179-O', 'women)-O', 'or-O', 'BRCA2-O', '(28-O', 'women).-O', 'The-O', 'control-O', 'women-O', 'were-O', 'enrolled-O', 'regardless-O', 'of-O', 'whether-O', 'or-O', 'not-O', 'they-O', 'had-O', 'either-O', 'mutation.-O']
['Lifetime-O', 'histories-O', 'of-O', 'oral-contraceptive-O', 'use-O', 'were-O', 'obtained-O', 'by-O', 'interview-O', 'or-O', 'by-O', 'written-O', 'questionnaire-O', 'and-O', 'were-O', 'compared-O', 'between-O', 'patients-O', 'and-O', 'control-O', 'women,-O', 'after-O', 'adjustment-O', 'for-O', 'year-O', 'of-O', 'birth-O', 'and-O', 'parity.-O']
['RESULTS-O', 'The-O', 'adjusted-O', 'odds-O', 'ratio-O', 'for-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'associated-O', 'with-O', 'any-O', 'past-O', 'use-O', 'of-O', 'oral-O', 'contraceptives-O', 'was-O', '0.-O']
['5-O', '(95-O', 'percent-O', 'confidence-O', 'interval,-O', '0.-O']
['3-O', 'to-O', '0.-O']
['8).-O', 'The-O', 'risk-O', 'decreased-O', 'with-O', 'increasing-O', 'duration-O', 'of-O', 'use-O', '(P-O', 'for-O', 'trend,-O', '<-O', '0.-O']
['001)-O', 'use-O', 'for-O', 'six-O', 'or-O', 'more-O', 'years-O', 'was-O', 'associated-O', 'with-O', 'a-O', '60-O', 'percent-O', 'reduction-O', 'in-O', 'risk-O']
['Oral-contraceptive-O', 'use-O', 'protected-O', 'against-O', 'ovarian-B-SpecificDisease', 'cancer,-I-SpecificDisease', 'both-O', 'for-O', 'carriers-O', 'of-O', 'the-O', 'BRCA1-O', 'mutation-O', '(odds-O', 'ratio,-O', '0.-O']
['5;-O', '95-O', 'percent-O', 'confidence-O', 'interval,-O', '0.-O']
['3-O', 'to-O', '0.-O']
['9)-O', 'and-O', 'for-O', 'carriers-O', 'of-O', 'the-O', 'BRCA2-O', 'mutation-O', '(odds-O', 'ratio,-O', '0.-O']
['4;-O', '95-O', 'percent-O', 'confidence-O', 'interval,-O', '0.-O']
['2-O', 'to-O', '1.-O']
['1).-O', 'CONCLUSIONS-O', 'Oral-contraceptive-O', 'use-O', 'may-O', 'reduce-O', 'the-O', 'risk-O', 'of-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'in-O', 'women-O', 'with-O', 'pathogenic-O', 'mutations-O', 'in-O', 'the-O', 'BRCA1-O', 'or-O', 'BRCA2-O', 'gene-O']
['A-O', 'deletion-O', 'mutation-O', 'in-O', 'COL17A1-O', 'in-O', 'five-O', 'Austrian-O', 'families-O', 'with-O', 'generalized-B-SpecificDisease', 'atrophic-I-SpecificDisease', 'benign-I-SpecificDisease', 'epidermolysis-I-SpecificDisease', 'bullosa-I-SpecificDisease', 'represents-O', 'propagation-O', 'of-O', 'an-O', 'ancestral-O', 'allele.-O']
['Patients-O', 'with-O', 'generalized-O', 'atrophic-O', 'benign-B-SpecificDisease', 'epidermolysis-O', 'bullosa,-I-SpecificDisease', 'a-O', 'usually-O', 'nonlethal-O', 'form-O', 'of-O', 'junctional-O', 'epidermolysis-O', 'bullosa,-I-SpecificDisease', 'have-O', 'generalized-O', 'blistering,-O', 'nail-O', 'dystrophy,-O', 'patchy-O', 'alopecia,-O', 'and-O', 'dental-O', 'abnormalities.-O', 'Skin-O', 'fragility-O', 'in-O', 'most-O', 'cases-O', 'is-O', 'due-O', 'to-O', 'mutations-O', 'in-O', 'the-O', 'gene-O', 'encoding-O', 'type-O', 'XVII-O', 'collagen-O', '(COL17A1).-O', 'Recently,-O', 'we-O', 'reported-O', 'five-O', 'Austrian-O', 'families-O', 'with-O', 'generalized-O', 'atrophic-O', 'benign-B-SpecificDisease', 'epidermolysis-O', 'bullosa-O', 'who-O', 'share-O', 'the-O', 'same-O', 'COL17A1-O', 'mutation.-O']
['Affected-O', 'individuals-O', 'in-O', 'three-O', 'families-O', 'are-O', 'homozygous-O', 'for-O', '4003delTC,-O', 'whereas-O', 'those-O', 'in-O', 'two-O', 'others-O', 'are-O', 'compound-O', 'heterozygotes.-O']
['To-O', 'determine-O', 'if-O', 'the-O', 'occurrence-O', 'of-O', '4003delTC-O', 'in-O', 'these-O', 'unrelated-O', 'families-O', 'signifies-O', 'propagation-O', 'of-O', 'an-O', 'ancestral-O', 'allele-O', 'or-O', 'a-O', 'mutational-O', 'hot-O', 'spot,-O', 'haplotypes-O', 'were-O', 'determined-O', 'for-O', 'polymorphisms-O', 'both-O', 'within-O', 'and-O', 'flanking-O', 'COL17A1-O']
['Five-O', 'intragenic-O', 'polymorphisms-O', 'were-O', 'chosen-O', 'based-O', 'on-O', 'their-O', 'informativeness.-O']
['One-O', 'of-O', 'these,-O', 'not-O', 'previously-O', 'reported,-O', 'was-O', '2988-O', 'A-O', 'or-O', 'C-O', 'that-O', 'introduces-O', 'a-O', 'new-O', 'restriction-O', 'site-O', 'for-O', 'Eco0109-O', 'I.-O']
['All-O', 'the-O', '4003delTC-O', 'alleles-O', 'showed-O', 'the-O', 'same-O', 'haplotype-O', 'for-O', 'these-O', 'five-O', 'polymorphic-O', 'markers.-O']
['Fourteen-O', 'microsatellite-O', 'polymorphisms-O', 'were-O', 'selected-O', 'based-O', 'on-O', 'their-O', 'high-O', 'heterozygosity-O', 'and-O', 'their-O', 'location-O', 'within-O', '10q23-q25-O', 'near-O', 'COL17A1-O']
['Three-O', 'families-O', 'shared-O', 'microsatellite-O', 'polymorphisms-O', 'covering-O', 'at-O', 'most-O', '19-O', 'cM,-O', 'whereas-O', 'the-O', 'others-O', 'shared-O', 'smaller-O', 'regions-O', 'consistent-O', 'with-O', 'cross-over-O', 'events-O', 'during-O', 'passage-O', 'of-O', 'this-O', 'mutation-O', 'through-O', 'several-O', 'generations.-O']
['These-O', 'results-O', 'indicate-O', 'that-O', '4003delTC-O', 'occurs-O', 'on-O', 'a-O', 'single-O', 'ancestral-O', 'allele..-O']
['A-O', 'novel-O', 'missense-O', 'mutation-O', 'in-O', 'patients-O', 'from-O', 'a-O', 'retinoblastoma-B-SpecificDisease', 'pedigree-O', 'showing-O', 'only-O', 'mild-O', 'expression-O', 'of-O', 'the-O', 'tumor-B-Modifier', 'phenotype.-O']
['We-O', 'have-O', 'used-O', 'single-O', 'strand-O', 'conformation-O', 'polymorphism-O', 'analysis-O', 'to-O', 'study-O', 'the-O', '27-O', 'exons-O', 'of-O', 'the-O', 'RB1-O', 'gene-O', 'in-O', 'individuals-O', 'from-O', 'a-O', 'family-O', 'showing-O', 'mild-O', 'expression-O', 'of-O', 'the-O', 'retinoblastoma-B-Modifier', 'phenotype.-O']
['In-O', 'this-O', 'family-O', 'affected-O', 'individuals-O', 'developed-O', 'unilateral-O', 'tumors-B-DiseaseClass', 'and,-O', 'as-O', 'a-O', 'result-O', 'of-O', 'linkage-O', 'analysis,-O', 'unaffected-O', 'mutation-O', 'carriers-O', 'were-O', 'also-O', 'identified-O', 'within-O', 'the-O', 'pedigree.-O']
['A-O', 'single-O', 'band-O', 'shift-O', 'using-O', 'SSCP-O', 'was-O', 'identified-O', 'in-O', 'exon-O', '21-O', 'which-O', 'resulted-O', 'in-O', 'a-O', 'missense-O', 'mutation-O', 'converting-O', 'a-O', 'cys--O', '>-O', 'arg-O', 'at-O', 'nucleotide-O', 'position-O', '28-O', 'in-O', 'the-O', 'exon.-O']
['The-O', 'mutation-O', 'destroyed-O', 'an-O', 'NdeI-O', 'restriction-O', 'enzyme-O', 'site.-O']
['Analysis-O', 'of-O', 'all-O', 'family-O', 'members-O', 'demonstrated-O', 'that-O', 'the-O', 'missense-O', 'mutation-O', 'co-segregated-O', 'with-O', 'patients-O', 'with-O', 'tumors-B-DiseaseClass', 'or-O', 'who,-O', 'as-O', 'a-O', 'result-O', 'of-O', 'linkage-O', 'analysis-O', 'had-O', 'been-O', 'predicted-O', 'to-O', 'carry-O', 'the-O', 'predisposing-O', 'mutation.-O']
['These-O', 'observations-O', 'point-O', 'to-O', 'another-O', 'region-O', 'of-O', 'the-O', 'RB1-O', 'gene-O', 'where-O', 'mutations-O', 'only-O', 'modify-O', 'the-O', 'function-O', 'of-O', 'the-O', 'gene-O', 'and-O', 'raise-O', 'important-O', 'questions-O', 'for-O', 'genetic-O', 'counseling-O', 'in-O', 'families-O', 'with-O', 'these-O', 'distinctive-O', 'phenotypes..-O']
['Identification-O', 'of-O', 'three-O', 'novel-O', 'mutations-O', 'and-O', 'a-O', 'high-O', 'frequency-O', 'of-O', 'the-O', 'Arg778Leu-O', 'mutation-O', 'in-O', 'Korean-O', 'patients-O', 'with-O', 'Wilson-B-SpecificDisease', 'disease.-I-SpecificDisease', 'Four-O', 'mutations--O', 'R778L,-O', 'A874V,-O', 'L1083F,-O', 'and-O', '2304delC--O', 'in-O', 'the-O', 'copper-transporting-O', 'enzyme,-O', 'P-type-O', 'ATPase-O', '(ATP7B),-O', 'were-O', 'identified-O', 'in-O', 'Korean-O', 'Patients-O', 'with-O', 'Wilson-B-SpecificDisease', 'disease.-I-SpecificDisease', 'Arg778Leu,-O', 'the-O', 'most-O', 'frequently-O', 'reported-O', 'mutation-O', 'of-O', 'this-O', 'enzyme,-O', 'was-O', 'found-O', 'in-O', 'six-O', 'of-O', 'eight-O', 'unrelated-O', 'patients-O', 'studied,-O', 'an-O', 'allele-O', 'frequency-O', 'of-O', '37.-O']
['5%-O', 'which-O', 'is-O', 'considerably-O', 'higher-O', 'than-O', 'those-O', 'in-O', 'other-O', 'Asian-O', 'populations.-O']
['The-O', 'novel-O', 'single-O', 'nucleotide-O', 'deletion,-O', '2304delC,-O', 'was-O', 'found-O', 'in-O', 'one-O', 'patient.-O']
['Since-O', 'a-O', 'mutation-O', 'at-O', 'cDNA-O', 'nucleotide-O', '2302-O', '(2302insC)-O', 'had-O', 'been-O', 'previously-O', 'described,-O', 'this-O', 'region-O', 'of-O', 'the-O', 'ATP7B-O', 'gene-O', 'may-O', 'be-O', 'susceptible-O', 'to-O', 'gene-O', 'rearrangements-O', 'causing-O', 'Wilson-B-Modifier', 'disease.-I-Modifier']
['The-O', 'hemochromatosis-B-Modifier', '845-O', 'G-->A-O', 'and-O', '187-O', 'C-->G-O', 'mutations:-O', 'prevalence-O', 'in-O', 'non-Caucasian-O', 'populations.-O']
['Hemochromatosis,-B-SpecificDisease', 'the-O', 'inherited-B-DiseaseClass', 'disorder-I-DiseaseClass', 'of-I-DiseaseClass', 'iron-O', 'metabolism,-O', 'leads,-O', 'if-O', 'untreated,-O', 'to-O', 'progressive-O', 'iron-O', 'overload-O', 'and-O', 'premature-O', 'death.-O', 'The-O', 'hemochromatosis-B-Modifier', 'gene,-O', 'HFE,-O', 'recently-O', 'has-O', 'been-O', 'identified,-O', 'and-O', 'characterization-O', 'of-O', 'this-O', 'gene-O', 'has-O', 'shown-O', 'that-O', 'it-O', 'contains-O', 'two-O', 'mutations-O', 'that-O', 'result-O', 'in-O', 'amino-O', 'acid-O', 'substitutions-cDNA-O', 'nucleotides-O', '845-O', 'G--O', '>O', 'A-O', '(C282Y)-O', 'and-O', '187-O', 'C--O', '>O', 'G-O', '(H63D).-O', 'Although-O', 'hemochromatosis-O', 'is-O', 'common-O', 'in-O', 'Caucasians,-O', 'affecting-O', '>O', '=O', '1/300-O', 'individuals-O', 'of-O', 'northern-O', 'European-O', 'origin,-O', 'it-O', 'has-O', 'not-O', 'been-O', 'recognized-O', 'in-O', 'other-O', 'populations.-O']
['The-O', 'present-O', 'study-O', 'used-O', 'PCR-O', 'and-O', 'restriction-enzyme-O', 'digestion-O', 'to-O', 'analyze-O', 'the-O', 'frequency-O', 'of-O', 'the-O', '845-O', 'G--', '>-O', 'A-O', 'and-O', '187-O', 'C--', '>-O', 'G-O', 'mutations-O', 'in-O', 'HLA-typed-O', 'samples-O', 'from-O', 'non-Caucasian-O', 'populations,-O', 'comprising-O', 'Australian-O', 'Aboriginal,-O', 'Chinese,-O', 'and-O', 'Pacific-O', 'Islanders.-O']
['Results-O', 'showed-O', 'that-O', 'the-O', '845-O', 'G--O', '>', 'A-O', 'mutation-O', 'was-O', 'present-O', 'in-O', 'these-O', 'populations-O', '(allele-O', 'frequency-O', '0.-O']
['32%)-O', 'and,-O', 'furthermore,-O', 'it-O', 'was-O', 'always-O', 'seen-O', 'in-O', 'conjunction-O', 'with-O', 'HLA-O', 'haplotypes-O', 'common-O', 'in-O', 'Caucasians,-O', 'suggesting-O', 'that-O', '845-O', 'G--->-O', 'A-O', 'may-O', 'have-O', 'been-O', 'introduced-O', 'into-O', 'these-O', 'populations-O', 'by-O', 'Caucasian-O', 'admixture.-O']
['187-O', 'C--O', '>-O', 'G-O', 'was-O', 'present-O', 'at-O', 'an-O', 'allele-O', 'frequency-O', 'of-O', '2.-O']
['68%-O', 'in-O', 'the-O', 'two-O', 'populations-O', 'analyzed-O', '(Australian-O', 'Aboriginal-O', 'and-O', 'Chinese).-O', 'In-O', 'the-O', 'Australian-O', 'Aboriginal-O', 'samples,-O', '187-O', 'C--O', '>O', 'G-O', 'was-O', 'found-O', 'to-O', 'be-O', 'associated-O', 'with-O', 'HLA-B-Modifier', 'haplotypes-O', 'common-O', 'in-O', 'Caucasians,-O', 'suggesting-O', 'that-O', 'it-O', 'was-O', 'introduced-O', 'by-O', 'recent-O', 'admixture.-O']
['In-O', 'the-O', 'Chinese-O', 'samples-O', 'analyzed,-O', '187-O', 'C--', '>O', 'G-O', 'was-O', 'present-O', 'in-O', 'association-O', 'with-O', 'a-O', 'wide-O', 'variety-O', 'of-O', 'HLA-O', 'haplotypes,-O', 'showing-O', 'this-O', 'mutation-O', 'to-O', 'be-O', 'widespread-O', 'and-O', 'likely-O', 'to-O', 'predate-O', 'the-O', 'more-O', 'genetically-O', 'restricted-O', '845-O', 'G--', '>O', 'A-O', 'mutation.-O']
['Genetic-O', 'heterogeneity-O', 'and-O', 'penetrance-O', 'analysis-O', 'of-O', 'the-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'genes-O', 'in-O', 'breast-B-Modifier', 'cancer-I-Modifier', 'families.-O']
['The-O', 'Breast-B-Modifier', 'Cancer-I-Modifier', 'Linkage-O', 'Consortium.-O']
['The-O', 'contribution-O', 'of-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'to-O', 'inherited-B-Modifier', 'breast-I-Modifier', 'cancer-I-Modifier', 'was-O', 'assessed-O', 'by-O', 'linkage-O', 'and-O', 'mutation-O', 'analysis-O', 'in-O', '237-O', 'families,-O', 'each-O', 'with-O', 'at-O', 'least-O', 'four-O', 'cases-O', 'of-O', 'breast-B-Modifier', 'cancer,-I-Modifier', 'collected-O', 'by-O', 'the-O', 'Breast-O', 'Cancer-O', 'Linkage-O', 'Consortium.-O']
['Families-O', 'were-O', 'included-O', 'without-O', 'regard-O', 'to-O', 'the-O', 'occurrence-O', 'of-O', 'ovarian-B-SpecificDisease', 'or-O', 'other-O', 'cancers.-B-DiseaseClass', 'Overall,-O', 'disease-O', 'was-O', 'linked-O', 'to-O', 'BRCA1-O', 'in-O', 'an-O', 'estimated-O', '52%-O', 'of-O', 'families,-O', 'to-O', 'BRCA2-O', 'in-O', '32%-O', 'of-O', 'families,-O', 'and-O', 'to-O', 'neither-O', 'gene-O', 'in-O', '16%-O', '(95%-O', 'confidence-O', 'interval-O', '[CI]-O', '6%-O', '-28%),-O', 'suggesting-O', 'other-O', 'predisposition-O', 'genes.-O']
['The-O', 'majority-O', '(81%)-O', 'of-O', 'the-O', 'breast-ovarian-B-Modifier', 'cancer-I-Modifier', 'families-O', 'were-O', 'due-O', 'to-O', 'BRCA1,-O', 'with-O', 'most-O', 'others-O', '(14%)-O', 'due-O', 'to-O', 'BRCA2.-O']
['Conversely,-O', 'the-O', 'majority-O', 'of-O', 'families-O', 'with-O', 'male-B-Modifier', 'and-I-Modifier', 'female-B-Modifier', 'breast-I-Modifier', 'cancer-I-Modifier', 'were-O', 'due-O', 'to-O', 'BRCA2-O', '(76%).-O', 'The-O', 'largest-O', 'proportion-O', '(67%)-O', 'of-O', 'families-O', 'due-O', 'to-O', 'other-O', 'genes-O', 'was-O', 'found-O', 'in-O', 'families-O', 'with-O', 'four-O', 'or-O', 'five-O', 'cases-O', 'of-O', 'female-B-SpecificDisease', 'breast-I-SpecificDisease', 'cancer-I-SpecificDisease', 'only.-O']
['These-O', 'estimates-O', 'were-O', 'not-O', 'substantially-O', 'affected-O', 'either-O', 'by-O', 'changing-O', 'the-O', 'assumed-O', 'penetrance-O', 'model-O', 'for-O', 'BRCA1-O', 'or-O', 'by-O', 'including-O', 'or-O', 'excluding-O', 'BRCA1-O', 'mutation-O', 'data.-O']
['Among-O', 'those-O', 'families-O', 'with-O', 'disease-O', 'due-O', 'to-O', 'BRCA1-O', 'that-O', 'were-O', 'tested-O', 'by-O', 'one-O', 'of-O', 'the-O', 'standard-O', 'screening-O', 'methods,-O', 'mutations-O', 'were-O', 'detected-O', 'in-O', 'the-O', 'coding-O', 'sequence-O', 'or-O', 'splice-O', 'sites-O', 'in-O', 'an-O', 'estimated-O', '63%-O', '(95%-O', 'CI-O', '51%-O', '-77%).-O', 'The-O', 'estimated-O', 'sensitivity-O', 'was-O', 'identical-O', 'for-O', 'direct-O', 'sequencing-O', 'and-O', 'other-O', 'techniques.-O']
['The-O', 'penetrance-O', 'of-O', 'BRCA2-O', 'was-O', 'estimated-O', 'by-O', 'maximizing-O', 'the-O', 'LOD-O', 'score-O', 'in-O', 'BRCA2-O', 'mutation-O', 'families,-O', 'over-O', 'all-O', 'possible-O', 'penetrance-O', 'functions.-O']
['The-O', 'estimated-O', 'cumulative-O', 'risk-O', 'of-O', 'breast-B-SpecificDisease', 'cancer-I-SpecificDisease', 'reached-O', '28%-O', '(95%-O', 'CI-O', '9%-O', '-44%)-O', 'by-O', 'age-O', '50-O', 'years-O', 'and-O', '84%-O', '(95%-O', 'CI-O', '43%-O', '-95%)-O', 'by-O', 'age-O', '70-O', 'years.-O']
['The-O', 'corresponding-O', 'ovarian-B-Modifier', 'cancer-I-Modifier', 'risks-O', 'were-O', '0.-O']
['4%-O', '(95%-O', 'CI-O', '0%-O', '-1%)-O', 'by-O', 'age-O', '50-O', 'years-O', 'and-O', '27%-O', '(95%-O', 'CI-O', '0%-O', '-47%)-O', 'by-O', 'age-O', '70-O', 'years.-O']
['The-O', 'lifetime-O', 'risk-O', 'of-O', 'breast-B-SpecificDisease', 'cancer-I-SpecificDisease', 'appears-O', 'similar-O', 'to-O', 'the-O', 'risk-O', 'in-O', 'BRCA1-O', 'carriers,-O', 'but-O', 'there-O', 'was-O', 'some-O', 'suggestion-O', 'of-O', 'a-O', 'lower-O', 'risk-O', 'in-O', 'BRCA2-O', 'carriers-O', '<-O', '50-O', 'years-O', 'of-O', 'age.-O']
['Susceptibility-O', 'to-O', 'ankylosing-B-SpecificDisease', 'spondylitis-I-SpecificDisease', 'in-O', 'twins:-O', 'the-O', 'role-O', 'of-O', 'genes,-O', 'HLA,-O', 'and-O', 'the-O', 'environment.-O']
['OBJECTIVE-O', 'To-O', 'determine-O', 'the-O', 'relative-O', 'effects-O', 'of-O', 'genetic-O', 'and-O', 'environmental-O', 'factors-O', 'in-O', 'susceptibility-O', 'to-O', 'ankylosing-B-SpecificDisease', 'spondylitis-I-SpecificDisease', '(AS).-I-SpecificDisease', 'METHODS-O', 'Twins-O', 'with-O', 'AS-I-SpecificDisease', 'were-O', 'identified-O', 'from-O', 'the-O', 'Royal-O', 'National-O', 'Hospital-O', 'for-O', 'Rheumatic-O', 'Diseases-O', 'database.-O']
['Clinical-O', 'and-O', 'radiographic-O', 'examinations-O', 'were-O', 'performed-O', 'to-O', 'establish-O', 'diagnoses,-O', 'and-O', 'disease-O', 'severity-O', 'was-O', 'assessed-O', 'using-O', 'a-O', 'combination-O', 'of-O', 'validated-O', 'scoring-O', 'systems.-O']
['HLA-O', 'typing-O', 'for-O', 'HLA-B27,-O', 'HLA-B60,-O', 'and-O', 'HLA-DR1-O', 'was-O', 'performed-O', 'by-O', 'polymerase-O', 'chain-O', 'reaction-O', 'with-O', 'sequence-specific-O', 'primers,-O', 'and-O', 'zygosity-O', 'was-O', 'assessed-O', 'using-O', 'microsatellite-O', 'markers.-O']
['Genetic-O', 'and-O', 'environmental-O', 'variance-O', 'components-O', 'were-O', 'assessed-O', 'with-O', 'the-O', 'program-O', 'Mx,-O', 'using-O', 'data-O', 'from-O', 'this-O', 'and-O', 'previous-O', 'studies-O', 'of-O', 'twins-O', 'with-O', 'AS.-O', 'RESULTS-O', 'Six-O', 'of-O', '8-O', 'monozygotic-O', '(MZ)-O', 'twin-O', 'pairs-O', 'were-O', 'disease-O', 'concordant,-O', 'compared-O', 'with-O', '4-O', 'of-O', '15-O', 'B27-positive-O', 'dizygotic-O', '(DZ)-O', 'twin-O', 'pairs-O', '(27%)-O', 'and-O', '4-O', 'of-O', '32-O', 'DZ-O', 'twin-O', 'pairs-O', 'overall-O', '(12.-O']
['5%)-O', 'Nonsignificant-O', 'increases-O', 'in-O', 'similarity-O', 'with-O', 'regard-O', 'to-O', 'age-O', 'at-O', 'disease-O', 'onset-O', 'and-O', 'all-O', 'of-O', 'the-O', 'disease-O', 'severity-O', 'scores-O', 'assessed-O', 'were-O', 'noted-O', 'in-O', 'disease-concordant-O', 'MZ-O', 'twins-O', 'compared-O', 'with-O', 'concordant-O', 'DZ-O', 'twins.-O']
['HLA-B27-O', 'and-O', 'B60-O', 'were-O', 'associated-O', 'with-O', 'the-O', 'disease-O', 'in-O', 'probands,-O', 'and-O', 'the-O', 'rate-O', 'of-O', 'disease-O', 'concordance-O', 'was-O', 'significantly-O', 'increased-O', 'among-O', 'DZ-O', 'twin-O', 'pairs-O', 'in-O', 'which-O', 'the-O', 'co-twin-O', 'was-O', 'positive-O', 'for-O', 'both-O', 'B27-O', 'and-O', 'DR1.-O']
['Additive-O', 'genetic-B-DiseaseClass', 'effects-O', 'were-O', 'estimated-O', 'to-O', 'contribute-O', '97%-O', 'of-O', 'the-O', 'population-O', 'variance.-O']
['CONCLUSION-O', 'Susceptibility-O', 'to-O', 'AS-B-SpecificDisease', 'is-O', 'largely-O', 'genetically-O', 'determined,-O', 'and-O', 'the-O', 'environmental-O', 'trigger-O', 'for-O', 'the-O', 'disease-O', 'is-O', 'probably-O', 'ubiquitous.-O']
['HLA-B27-O', 'accounts-O', 'for-O', 'a-O', 'minority-O', 'of-O', 'the-O', 'overall-O', 'genetic-O', 'susceptibility-O', 'to-O', 'AS.-B-SpecificDisease']
['Genetic-O', 'mapping-O', 'of-O', 'the-O', 'copper-B-Modifier', 'toxicosis-I-Modifier', 'locus-O', 'in-O', 'Bedlington-O', 'terriers-O', 'to-O', 'dog-O', 'chromosome-O', '10,-O', 'in-O', 'a-O', 'region-O', 'syntenic-O', 'to-O', 'human-O', 'chromosome-O', 'region-O', '2p13-p16.-O']
['Abnormal-O', 'hepatic-O', 'copper-O', 'accumulation-O', 'is-O', 'recognized-O', 'as-O', 'an-O', 'inherited-B-DiseaseClass', 'disorder-I-DiseaseClass', 'in-O', 'man,-O', 'mouse,-O', 'rat-O', 'and-O', 'dog.-O']
['The-O', 'major-O', 'cause-O', 'of-O', 'hepatic-O', 'copper-O', 'accumulation-O', 'in-O', 'man-O', 'is-O', 'a-O', 'dysfunctional-O', 'ATP7B-O', 'gene,-O', 'causing-O', 'Wilson-B-SpecificDisease', 'disease-I-SpecificDisease', '(WD)-I-SpecificDisease.', 'Mutations-O', 'in-O', 'the-O', 'ATP7B-O', 'genes-O', 'have-O', 'also-O', 'been-O', 'demonstrated-O', 'in-O', 'mouse-O', 'and-O', 'rat.-O']
['The-O', 'ATP7B-O', 'gene-O', 'has-O', 'been-O', 'excluded-O', 'in-O', 'the-O', 'much-O', 'rarer-O', 'human-O', 'copper-O', 'overload-O', 'disease-B-DiseaseClass', 'non-Indian-O', 'childhood-O', 'cirrhosis,-I-DiseaseClass', 'indicating-O', 'genetic-O', 'heterogeneity.-O']
['By-O', 'investigating-O', 'the-O', 'common-O', 'autosomal-O', 'recessive-O', 'copper-O', 'toxicosis-O', '(CT)-O', 'in-O', 'Bedlington-O', 'terriers,-O', 'we-O', 'have-O', 'identified-O', 'a-O', 'new-O', 'locus-O', 'involved-O', 'in-O', 'progressive-O', 'liver-O', 'disease.-O', 'We-O', 'examined-O', 'whether-O', 'the-O', 'WD-B-Modifier', 'gene-O', 'ATP7B-O', 'was-O', 'also-O', 'causative-O', 'for-O', 'CT-O', 'by-O', 'investigating-O', 'the-O', 'chromosomal-O', 'co-localization-O', 'of-O', 'ATP7B-O', 'and-O', 'C04107,-O', 'using-O', 'fluorescence-O', 'in-O', 'situ-O', 'hybridization-O', '(FISH).-O', 'C04107-O', 'is-O', 'an-O', 'anonymous-O', 'microsatellite-O', 'marker-O', 'closely-O', 'linked-O', 'to-O', 'CT.-O', 'However,-O', 'BAC-O', 'clones-O', 'containing-O', 'ATP7B-O', 'and-O', 'C04107,-O', 'mapped-O', 'to-O', 'the-O', 'canine-O', 'chromosome-O', 'regions-O', 'CFA22q11-O', 'and-O', 'CFA10q26,-O', 'respectively,-O', 'demonstrating-O', 'that-O', 'WD-O', 'cannot-O', 'be-O', 'homologous-O', 'to-O', 'CT.-O', 'The-O', 'copper-O', 'transport-O', 'genes-O', 'CTR1-O', 'and-O', 'CTR2-O', 'were-O', 'also-O', 'excluded-O', 'as-O', 'candidate-O', 'genes-O', 'for-O', 'CT-O', 'since-O', 'they-O', 'both-O', 'mapped-O', 'to-O', 'canine-O', 'chromosome-O', 'region-O', 'CFA11q22.-O']
['2-O', '22.-O']
['5.-O']
['A-O', 'transcribed-O', 'sequence-O', 'identified-O', 'from-O', 'the-O', 'C04107-containing-O', 'BAC-O', 'was-O', 'found-O', 'to-O', 'be-O', 'homologous-O', 'to-O', 'a-O', 'gene-O', 'expressed-O', 'from-O', 'human-O', 'chromosome-O', '2p13-p16,-O', 'a-O', 'region-O', 'devoid-O', 'of-O', 'any-O', 'positional-O', 'candidate-O', 'genes.-O']
['Ataxia-telangiectasia:-B-SpecificDisease', 'identification-O', 'and-O', 'detection-O', 'of-O', 'founder-effect-O', 'mutations-O', 'in-O', 'the-O', 'ATM-O', 'gene-O', 'in-O', 'ethnic-O', 'populations.-O']
['To-O', 'facilitate-O', 'the-O', 'evaluation-O', 'of-O', 'ATM-O', 'heterozygotes-O', 'for-O', 'susceptibility-O', 'to-O', 'other-O', 'diseases,-O', 'such-O', 'as-O', 'breast-B-Modifier', 'cancer,-I-Modifier', 'we-O', 'have-O', 'attempted-O', 'to-O', 'define-O', 'the-O', 'most-O', 'common-O', 'mutations-O', 'and-O', 'their-O', 'frequencies-O', 'in-O', 'ataxia-telangiectasia-B-Modifier', '(A-T)-O', 'homozygotes-O', 'from-O', '10-O', 'ethnic-O', 'populations.-O']
['Both-O', 'genomic-O', 'mutations-O', 'and-O', 'their-O', 'effects-O', 'on-O', 'cDNA-O', 'were-O', 'characterized.-O']
['Protein-truncation-O', 'testing-O', 'of-O', 'the-O', 'entire-O', 'ATM-O', 'cDNA-O', 'detected-O', '92-O', '(66%)-O', 'truncating-O', 'mutations-O', 'in-O', '140-O', 'mutant-O', 'alleles-O', 'screened.-O']
['The-O', 'haplotyping-O', 'of-O', 'patients-O', 'with-O', 'identical-O', 'mutations-O', 'indicates-O', 'that-O', 'almost-O', 'all-O', 'of-O', 'these-O', 'represent-O', 'common-O', 'ancestry-O', 'and-O', 'that-O', 'very-O', 'few-O', 'spontaneously-O', 'recurring-O', 'ATM-O', 'mutations-O', 'exist.-O']
['Assays-O', 'requiring-O', 'minimal-O', 'amounts-O', 'of-O', 'genomic-O', 'DNA-O', 'were-O', 'designed-O', 'to-O', 'allow-O', 'rapid-O', 'screening-O', 'for-O', 'common-O', 'ethnic-O', 'mutations.-O']
['These-O', 'rapid-O', 'assays-O', 'detected-O', 'mutations-O', 'in-O', '76%-O', 'of-O', 'Costa-O', 'Rican-O', 'patients-O', '(3),-O', '50%-O', 'of-O', 'Norwegian-O', 'patients-O', '(1),-O', '25%-O', 'of-O', 'Polish-O', 'patients-O', '(4),-O', 'and-O', '14%-O', 'of-O', 'Italian-O', 'patients-O', '(1),-O', 'as-O', 'well-O', 'as-O', 'in-O', 'patients-O', 'of-O', 'Amish/Mennonite-O', 'and-O', 'Irish-O', 'English-O', 'backgrounds.-O']
['Additional-O', 'mutations-O', 'were-O', 'observed-O', 'in-O', 'Japanese-O', 'Utah-O', 'Mormon,-O', 'and-O', 'African-O', 'American-O', 'patients.-O']
['These-O', 'assays-O', 'should-O', 'facilitate-O', 'screening-O', 'for-O', 'A-T-B-Modifier', 'heterozygotes-O', 'in-O', 'the-O', 'populations-O', 'studied..-O']
['Progression-O', 'of-O', 'somatic-O', 'CTG-O', 'repeat-O', 'length-O', 'heterogeneity-O', 'in-O', 'the-O', 'blood-O', 'cells-O', 'of-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', 'patients.-O']
['The-O', 'genetic-B-DiseaseClass', 'basis-O', 'of-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM)-O', 'is-O', 'the-O', 'expansion-O', 'of-O', 'an-O', 'unstable-O', 'CTG-O', 'repeat-O', 'in-O', 'the-O', '34-O', 'UTR-O', 'of-O', 'the-O', 'DM-B-Modifier', 'protein-O', 'kinase-O', 'gene-O', 'on-O', 'chromosome-O', '19.-O']
['One-O', 'of-O', 'the-O', 'principal-O', 'features-O', 'of-O', 'the-O', 'DM-B-Modifier', 'mutation-O', 'is-O', 'an-O', 'extraordinarily-O', 'high-O', 'level-O', 'of-O', 'somatic-O', 'mosaicism,-O', 'due-O', 'to-O', 'an-O', 'extremely-O', 'high-O', 'degree-O', 'of-O', 'somatic-O', 'instability-O', 'both-O', 'within-O', 'and-O', 'between-O', 'different-O', 'tissues.-O']
['This-O', 'instability-O', 'appears-O', 'to-O', 'be-O', 'biased-O', 'towards-O', 'further-O', 'expansion-O', 'and-O', 'continuous-O', 'throughout-O', 'the-O', 'life-O', 'of-O', 'an-O', 'individual,-O', 'features-O', 'that-O', 'could-O', 'be-O', 'associated-O', 'with-O', 'the-O', 'progressive-B-DiseaseClass', 'nature-O', 'of-O', 'the-O', 'disease.-I-DiseaseClass']
['Although-O', 'increasing-O', 'measured-O', 'allele-O', 'size-O', 'between-O', 'patients-O', 'clearly-O', 'correlates-O', 'with-O', 'an-O', 'increased-O', 'severity-O', 'of-O', 'symptoms-O', 'and-O', 'an-O', 'earlier-O', 'age-O', 'of-O', 'onset,-O', 'this-O', 'correlation-O', 'is-O', 'not-O', 'precise-O', 'and-O', 'measured-O', 'allele-O', 'length-O', 'cannot-O', 'be-O', 'used-O', 'as-O', 'an-O', 'accurate-O', 'predictor-O', 'of-O', 'age-O', 'of-O', 'onset.-O']
['In-O', 'order-O', 'to-O', 'further-O', 'characterize-O', 'the-O', 'dynamics-O', 'of-O', 'DM-B-Modifier', 'CTG-O', 'repeat-O', 'somatic-O', 'instability,-O', 'we-O', 'have-O', 'studied-O', 'repeat-O', 'length-O', 'changes-O', 'over-O', 'time-O', 'in-O', '111-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', 'patients-O', 'with-O', 'varying-O', 'clinical-O', 'severity-O', 'and-O', 'CTG-O', 'repeat-O', 'size-O', 'over-O', 'time-O', 'intervals-O', 'of-O', '1-7-O', 'years.-O']
['We-O', 'have-O', 'found-O', 'a-O', 'direct-O', 'progression-O', 'of-O', 'the-O', 'size-O', 'heterogeneity-O', 'over-O', 'time-O', 'related-O', 'to-O', 'initial-O', 'CTG-O', 'repeat-O', 'size-O', 'and-O', 'the-O', 'time-O', 'interval-O', 'and-O', 'always-O', 'biased-O', 'towards-O', 'further-O', 'expansion.-O']
['Attempts-O', 'to-O', 'mathematically-O', 'model-O', 'the-O', 'dynamics-O', 'have-O', 'proved-O', 'only-O', 'partially-O', 'successful-O', 'suggesting-O', 'that-O', 'individual-O', 'specific-O', 'genetic-B-DiseaseClass', 'and/or-O', 'environmental-O', 'factors-O', 'also-O', 'play-O', 'a-O', 'role-O', 'in-O', 'somatic-O', 'mosaicism..-O']
['Crystal-O', 'structure-O', 'of-O', 'the-O', 'hemochromatosis-B-Modifier', 'protein-O', 'HFE-O', 'and-O', 'characterization-O', 'of-O', 'its-O', 'interaction-O', 'with-O', 'transferrin-O', 'receptor.-O']
['HFE-O', 'is-O', 'an-O', 'MHC-related-O', 'protein-O', 'that-O', 'is-O', 'mutated-O', 'in-O', 'the-O', 'iron-overload-O', 'disease-O', 'hereditary-B-SpecificDisease', 'hemochromatosis.-I-SpecificDisease', 'HFE-O', 'binds-O', 'to-O', 'transferrin-O', 'receptor-O', '(TfR)-O', 'and-O', 'reduces-O', 'its-O', 'affinity-O', 'for-O', 'iron-loaded-O', 'transferrin,-O', 'implicating-O', 'HFE-O', 'in-O', 'iron-O', 'metabolism.-O']
['The-O', '2.-O']
['6-O', 'A-O', 'crystal-O', 'structure-O', 'of-O', 'HFE-B-SpecificDisease', 'reveals-O', 'the-O', 'locations-O', 'of-O', 'hemochromatosis-I-SpecificDisease', 'mutations-O', 'and-O', 'a-O', 'patch-O', 'of-O', 'histidines-O', 'that-O', 'could-O', 'be-O', 'involved-O', 'in-O', 'pH-dependent-O', 'interactions.-O']
['We-O', 'also-O', 'demonstrate-O', 'that-O', 'soluble-O', 'TfR-O', 'and-O', 'HFE-O', 'bind-O', 'tightly-O', 'at-O', 'the-O', 'basic-O', 'pH-O', 'of-O', 'the-O', 'cell-O', 'surface,-O', 'but-O', 'not-O', 'at-O', 'the-O', 'acidic-O', 'pH-O', 'of-O', 'intracellular-O', 'vesicles.-O']
['TfR-O', 'HFE-O', 'stoichiometry-O', '(2-O', '1)-O', 'differs-O', 'from-O', 'TfR-O', 'transferrin-O', 'stoichiometry-O', '(2-O', '2),-O', 'implying-O', 'a-O', 'different-O', 'mode-O', 'of-O', 'binding-O', 'for-O', 'HFE-O', 'and-O', 'transferrin-O', 'to-O', 'TfR,-O', 'consistent-O', 'with-O', 'our-O', 'demonstration-O', 'that-O', 'HFE,-O', 'transferrin,-O', 'and-O', 'TfR-O', 'form-O', 'a-O', 'ternary-O', 'complex.-O']
['The-O', 'chromosomal-O', 'order-O', 'of-O', 'genes-O', 'controlling-O', 'the-O', 'major-O', 'histocompatibility-O', 'complex,-O', 'properdin-O', 'factor-O', 'B,-O', 'and-O', 'deficiency-B-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'second-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'complement.-I-SpecificDisease', 'The-O', 'relationship-O', 'of-O', 'the-O', 'genes-O', 'coding-O', 'for-O', 'HLA-O', 'to-O', 'those-O', 'coding-O', 'for-O', 'properdin-O', 'Factor-O', 'B-O', 'allotypes-O', 'and-O', 'for-O', 'deficiency-B-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'second-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'complement-O', '(C2)-O', 'was-O', 'studied-O', 'in-O', 'families-O', 'of-O', 'patients-O', 'with-O', 'connective-O', 'tissue-O', 'disorders.-O']
['Patients-O', 'were-O', 'selected-O', 'because-O', 'they-O', 'were-O', 'heterozygous-O', 'or-O', 'homozygous-O', 'for-O', 'C2-B-SpecificDisease', 'deficiency.-I-SpecificDisease', '12-O', 'families-O', 'with-O', '15-O', 'matings-O', 'informative-O', 'for-O', 'C2-O', 'deficiency-O', 'were-O', 'found.-O']
['Of-O', '57-O', 'informative-O', 'meioses,-O', 'two-O', 'crossovers-O', 'were-O', 'noted-O', 'between-O', 'the-O', 'C2-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'gene-O', 'and-O', 'the-O', 'HLA-B-O', 'gene,-O', 'with-O', 'a-O', 'recombinant-O', 'fraction-O', 'of-O', '0.-O']
['035.-O']
['A-O', 'lod-O', 'score-O', 'of-O', '13-O', 'was-O', 'calculated-O', 'for-O', 'linkage-O', 'between-O', 'C2-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'and-O', 'HLA-B-O', 'at-O', 'a-O', 'maximum-O', 'likelihood-O', 'value-O', 'of-O', 'the-O', 'recombinant-O', 'fraction-O', 'of-O', '0.-O']
['04.-O']
['18-O', 'families-O', 'with-O', '21-O', 'informative-O', 'matings-O', 'for-O', 'both-O', 'properdin-O', 'Factor-O', 'B-O', 'allotype-O', 'and-O', 'HLA-B-O', 'were-O', 'found.-O']
['Of-O', '72-O', 'informative-O', 'meioses,-O', 'three-O', 'recombinants-O', 'were-O', 'found,-O', 'giving-O', 'a-O', 'recombinant-O', 'fraction-O', 'of-O', '0.-O']
['042.-O']
['A-O', 'lod-O', 'score-O', 'of-O', '16-O', 'between-O', 'HLA-B-O', 'and-O', 'Factor-O', 'B-O', 'allotypes-O', 'was-O', 'calculated-O', 'at-O', 'a-O', 'maximum-O', 'likelihood-O', 'value-O', 'of-O', 'the-O', 'recombinant-O', 'fraction-O', 'of-O', '0.-O']
['04.-O']
['A-O', 'crossover-O', 'was-O', 'shown-O', 'to-O', 'have-O', 'occurred-O', 'between-O', 'genes-O', 'for-O', 'Factor-O', 'B-O', 'and-O', 'HLA-D,-O', 'in-O', 'which-O', 'HLA-D-O', 'segregared-O', 'with-O', 'HLA-A-O', 'and-O', 'B-O', '.-O']
['These-O', 'studies-O', 'suggest-O', 'that-O', 'the-O', 'genes-O', 'for-O', 'Factor-O', 'B-O', 'and-O', 'C2-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'are-O', 'located-O', 'outside-O', 'those-O', 'for-O', 'HLA,-O', 'that-O', 'the-O', 'order-O', 'of-O', 'genese-O', 'is-O', 'HLA-A,-O', '-B,-O', '-D,-O', 'Factor-O', 'B-O', 'allotype,-O', 'C2-O', 'deficiency,-I-SpecificDisease', 'that-O', 'the-O', 'genes-O', 'coding-O', 'for-O', 'C2-O', 'deficiency-I-SpecificDisease', 'and-O', 'Factor-O', 'B-O', 'allotypes-O', 'are-O', 'approximately-O', '3--5-O', 'centimorgans-O', 'from-O', 'the-O', 'HLA-A-O', 'and-O', 'HLA-B-O', 'loci,-O', 'and-O', 'that-O', 'the-O', 'apparent-O', 'lack-O', 'of-O', 'recombinants-O', 'between-O', 'the-O', 'Factor-O', 'B-O', 'gene-O', 'and-O', 'C2-O', 'deficiency-I-SpecificDisease', 'gene-O', 'suggests-O', 'that-O', 'these-O', 'two-O', 'genes-O', 'lie-O', 'in-O', 'close-O', 'proximity-O', 'to-O', 'one-O', 'another.-O']
['Identification-O', 'of-O', 'a-O', 'novel-O', 'nonsense-O', 'mutation-O', 'and-O', 'a-O', 'missense-O', 'substitution-O', 'in-O', 'the-O', 'vasopressin-neurophysin-O', 'II-O', 'gene-O', 'in-O', 'two-O', 'Spanish-O', 'kindreds-O', 'with-O', 'familial-B-SpecificDisease', 'neurohypophyseal-B-SpecificDisease', 'diabetes-I-SpecificDisease', 'insipidus.-I-SpecificDisease', 'Familial-B-SpecificDisease', 'neurohypophyseal-B-SpecificDisease', 'diabetes-I-SpecificDisease', 'insipidus.-I-SpecificDisease', '(FNDI)-O', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'disease-I-DiseaseClass', 'caused-O', 'by-O', 'deficiency-B-DiseaseClass', 'in-O', 'the-O', 'antidiuretic-O', 'hormone-O', 'arginine-O', 'vasopressin-O', '(AVP)-O', 'encoded-O', 'by-O', 'the-O', 'AVP-neurophysin-O', 'II-O', '(AVP-NPII)-O', 'gene-O', 'on-O', 'chromosome-O', '20p13.-O']
['In-O', 'this-O', 'study,-O', 'we-O', 'analyzed-O', 'two-O', 'families-O', 'with-O', 'FNDI-B-SpecificDisease', 'using-O', 'direct-O', 'automated-O', 'fluorescent,-O', 'solid-O', 'phase,-O', 'single-stranded-O', 'DNA-O', 'sequencing-O', 'of-O', 'PCR-amplified-O', 'AVP-NPII-O', 'DNA.-O']
['In-O', 'one-O', 'of-O', 'the-O', 'families,-O', 'affected-O', 'individuals-O', 'presented-O', 'a-O', 'novel-O', 'nonsense-O', 'mutation-O', 'in-O', 'exon-O', '3-O', 'of-O', 'the-O', 'gene,-O', 'consisting-O', 'in-O', 'a-O', 'G-O', 'to-O', 'T-O', 'transition-O', 'at-O', 'nucleotide-O', '2101,-O', 'which-O', 'produces-O', 'a-O', 'stop-O', 'signal-O', 'in-O', 'codon-O', '82-O', '(Glu)-O', 'of-O', 'NPII.-O']
['The-O', 'premature-O', 'termination-O', 'eliminates-O', 'part-O', 'of-O', 'the-O', 'C-terminal-O', 'domain-O', 'of-O', 'NPII,-O', 'including-O', 'a-O', 'cysteine-O', 'residue-O', 'in-O', 'position-O', '85,-O', 'which-O', 'could-O', 'be-O', 'involved-O', 'in-O', 'the-O', 'correct-O', 'folding-O', 'of-O', 'the-O', 'prohormone.-O']
['In-O', 'the-O', 'second-O', 'family,-O', 'a-O', 'G279A-O', 'substitution-O', 'at-O', 'position-O', '-1-O', 'of-O', 'the-O', 'signal-O', 'peptide-O', 'was-O', 'observed-O', 'in-O', 'all-O', 'affected-O', 'individuals.-O']
['This-O', 'missense-O', 'mutation,-O', 'which-O', 'replaces-O', 'Ala-O', 'with-O', 'Thr,-O', 'is-O', 'frequent-O', 'among-O', 'FNDI-B-SpecificDisease', 'patients-O', 'and-O', 'is-O', 'thought-O', 'to-O', 'reduce-O', 'the-O', 'efficiency-O', 'of-O', 'cleavage-O', 'by-O', 'signal-O', 'peptidases..-O']
['The-O', 'R496H-O', 'mutation-O', 'of-O', 'arylsulfatase-O', 'A-O', 'does-O', 'not-O', 'cause-O', 'metachromatic-B-SpecificDisease', 'leukodystrophy.-I-SpecificDisease', 'Deficiency-O', 'of-O', 'arylsulfatase-O', 'A-O', '(ARSA)-O', 'enzyme-O', 'activity-O', 'causes-O', 'metachromatic-B-SpecificDisease', 'leukodystrophy-I-SpecificDisease', '(MLD).-B-SpecificDisease', 'A-O', 'number-O', 'of-O', 'ARSA-O', 'gene-O', 'mutations-O', 'responsible-O', 'for-O', 'MLD-B-SpecificDisease', 'have-O', 'been-O', 'identified.-O']
['Recently,-O', 'the-O', 'R496H-O', 'mutation-O', 'of-O', 'ARSA-O', 'was-O', 'proposed-O', 'to-O', 'be-O', 'a-O', 'cause-O', 'of-O', 'MLD-B-SpecificDisease', '(Draghia-O', 'et-O', 'al.,-O', '1997).-O', 'We-O', 'have-O', 'investigated-O', 'the-O', 'R496H-O', 'mutation-O', 'and-O', 'found-O', 'this-O', 'mutation-O', 'at-O', 'a-O', 'relatively-O', 'high-O', 'frequency-O', 'in-O', 'an-O', 'African-O', 'American-O', 'population-O', '(f-O', '=O', '0.-O']
['09,-O', 'n-O', '='-O', '61-O', 'subjects).-O', 'The-O', 'ARSA-O', 'enzyme-O', 'activity-O', 'in-O', 'subjects-O', 'with-O', 'and-O', 'without-O', 'the-O', 'R496H-O', 'mutation-O', 'was-O', 'determined-O', 'and-O', 'found-O', 'to-O', 'be-O', 'normal.-O']
['It-O', 'is-O', 'therefore-O', 'concluded-O', 'that-O', 'the-O', 'R496H-O', 'mutation-O', 'of-O', 'ARSA-O', 'does-O', 'not-O', 'negatively-O', 'influence-O', 'the-O', 'activity-O', 'of-O', 'ARSA-O', 'and-O', 'is-O', 'not-O', 'a-O', 'cause-O', 'of-O', 'MLD-B-SpecificDisease']
['Coincidence-O', 'of-O', 'two-O', 'novel-O', 'arylsulfatase-O', 'A-O', 'alleles-O', 'and-O', 'mutation-O', '459+1G>A-O', 'within-O', 'a-O', 'family-O', 'with-O', 'metachromatic-B-SpecificDisease', 'leukodystrophy:-I-SpecificDisease', 'molecular-O', 'basis-O', 'of-O', 'phenotypic-O', 'heterogeneity.-O']
['In-O', 'a-O', 'family-O', 'with-O', 'three-O', 'siblings,-O', 'one-O', 'developed-O', 'classical-O', 'late-O', 'infantile-B-SpecificDisease', 'metachromatic-I-SpecificDisease', 'leukodystrophy-I-SpecificDisease', '(MLD),-O', 'fatal-O', 'at-O', 'age-O', '5-O', 'years,-O', 'with-O', 'deficient-O', 'arylsulfatase-O', 'A-O', '(ARSA)-O', 'activity-O', 'and-O', 'increased-O', 'galactosylsulfatide-O', '(GS)-O', 'excretion.-O']
['The-O', 'two-O', 'other-O', 'siblings,-O', 'apparently-O', 'healthy-O', 'at-O', '12-O', '(1/2)-O', 'and-O', '15-O', 'years,-O', 'respectively,-O', 'and-O', 'their-O', 'father,-O', 'apparently-O', 'healthy-O', 'as-O', 'well,-O', 'presented-O', 'ARSA-O', 'and-O', 'GS-O', 'values-O', 'within-O', 'the-O', 'range-O', 'of-O', 'MLD-B-SpecificDisease', 'patients.-O']
['Mutation-O', 'screening-O', 'and-O', 'sequence-O', 'analysis-O', 'disclosed-O', 'the-O', 'involvement-O', 'of-O', 'three-O', 'different-O', 'ARSA-O', 'mutations-O', 'being-O', 'the-O', 'molecular-O', 'basis-O', 'of-O', 'intrafamilial-O', 'phenotypic-O', 'heterogeneity.-O']
['The-O', 'late-O', 'infantile-O', 'patient-O', 'inherited-O', 'from-O', 'his-O', 'mother-O', 'the-O', 'frequent-O', '0-type-O', 'mutation-O', '459-O', '+-O', '1G-O', '>-O', 'A,-O', 'and-O', 'from-O', 'his-O', 'father-O', 'a-O', 'novel,-O', 'single-O', 'basepair-O', 'microdeletion-O', 'of-O', 'guanine-O', 'at-O', 'nucleotide-O', '7-O', 'in-O', 'exon-O', '1-O', '(7delG).-O', 'The-O', 'two-O', 'clinically-O', 'unaffected-O', 'siblings-O', 'carried-O', 'the-O', 'maternal-O', 'mutation-O', '459-O', '+-O', '1G-O', '>-O', 'A-O', 'and,-O', 'on-O', 'their-O', 'paternal-O', 'allele,-O', 'a-O', 'novel-O', 'cytosine-O', 'to-O', 'thymidine-O', 'transition-O', 'at-O', 'nucleotide-O', '2435-O', 'in-O', 'exon-O', '8,-O', 'resulting-O', 'in-O', 'substitution-O', 'of-O', 'alanine-O', '464-O', 'by-O', 'valine-O', '(A464V).-O', 'The-O', 'fathers-O', 'genotype-O', 'thus-O', 'was-O', '7delG/A464V.-O']
['Mutation-O', 'A464V-O', 'was-O', 'not-O', 'found-O', 'in-O', '18-O', 'unrelated-O', 'MLD-B-Modifier', 'patients-O', 'and-O', '50-O', 'controls.-O']
['A464V-O', 'although-O', 'clearly-O', 'modifying-O', 'ARSA-O', 'and-O', 'GS-O', 'levels,-O', 'apparently-O', 'bears-O', 'little-O', 'significance-O', 'for-O', 'clinical-O', 'manifestation-O', 'of-O', 'MLD,-B-SpecificDisease', 'mimicking-O', 'the-O', 'frequent-O', 'ARSA-O', 'pseudodeficiency-O', 'allele.-O']
['Our-O', 'results-O', 'demonstrate-O', 'that-O', 'in-O', 'certain-O', 'genetic-O', 'conditions-O', 'MLD-like-B-SpecificDisease', 'ARSA-O', 'and-O', 'GS-B-Modifier', 'values-O', 'need-O', 'not-O', 'be-O', 'paralleled-O', 'by-O', 'clinical-O', 'disease,-O', 'a-O', 'finding-O', 'with-O', 'serious-O', 'diagnostic-O', 'and-O', 'prognostic-O', 'implications.-O']
['Moreover,-O', 'further-O', 'ARSA-O', 'alleles-O', 'functionally-O', 'similar-O', 'to-O', 'A464V-O', 'might-O', 'exist-O', 'which,-O', 'together-O', 'with-O', '0-type-O', 'mutations,-O', 'may-O', 'cause-O', 'pathological-O', 'ARSA-O', 'and-O', 'GS-O', 'levels,-O', 'but-O', 'not-O', 'clinical-O', 'outbreak-O', 'of-O', 'the-O', 'disease..-O']
['Missense-O', 'mutations-O', 'in-O', 'the-O', 'most-O', 'ancient-O', 'residues-O', 'of-O', 'the-O', 'PAX6-O', 'paired-O', 'domain-O', 'underlie-O', 'a-O', 'spectrum-O', 'of-O', 'human-O', 'congenital-O', 'eye-O', 'malformations.-O', 'Mutations-O', 'of-O', 'the-O', 'human-O', 'PAX6-O', 'gene-O', 'underlie-O', 'aniridia,-B-SpecificDisease', '(congenital-O', 'absence-O', 'of-O', 'the-O', 'iris),-I-SpecificDisease', 'a-O', 'rare-O', 'dominant-O', 'malformation-O', 'of-O', 'the-O', 'eye.-O', 'The-O', 'spectrum-O', 'of-O', 'PAX6-O', 'mutations-O', 'in-O', 'aniridia-B-Modifier', 'patients-O', 'is-O', 'highly-O', 'biased,-O', 'with-O', '92%-O', 'of-O', 'all-O', 'reported-O', 'mutations-O', 'leading-O', 'to-O', 'premature-O', 'truncation-O', 'of-O', 'the-O', 'protein-O', '(nonsense,-O', 'splicing,-O', 'insertions-O', 'and-O', 'deletions)-O', 'and-O', 'just-O', '2%-O', 'leading-O', 'to-O', 'substitution-O', 'of-O', 'one-O', 'amino-O', 'acid-O', 'by-O', 'another-O', '(missense).-O', 'The-O', 'extraordinary-O', 'conservation-O', 'of-O', 'the-O', 'PAX6-O', 'protein-O', 'at-O', 'the-O', 'amino-O', 'acid-O', 'level-O', 'amongst-O', 'vertebrates-O', 'predicts-O', 'that-O', 'pathological-O', 'missense-O', 'mutations-O', 'should-O', 'in-O', 'fact-O', 'be-O', 'common-O', 'even-O', 'though-O', 'they-O', 'are-O', 'hardly-O', 'ever-O', 'seen-O', 'in-O', 'aniridia-B-Modifier', 'patients.-O']
['This-O', 'indicates-O', 'that-O', 'there-O', 'is-O', 'a-O', 'heavy-O', 'ascertainment-O', 'bias-O', 'in-O', 'the-O', 'selection-O', 'of-O', 'patients-O', 'for-O', 'PAX6-O', 'mutation-O', 'analysis-O', 'and-O', 'that-O', 'the-O', 'missing-O', 'PAX6-O', 'missense-O', 'mutations-O', 'frequently-O', 'may-O', 'underlie-O', 'phenotypes-O', 'distinct-O', 'from-O', 'textbook-O', 'aniridia.-B-SpecificDisease', 'Here-O', 'we-O', 'present-O', 'four-O', 'novel-O', 'PAX6-O', 'missense-O', 'mutations,-O', 'two-O', 'in-O', 'association-O', 'with-O', 'atypical-O', 'phenotypes-O', 'ectopia-O', 'pupillae-B-SpecificDisease', '(displaced-O', 'pupils)-I-SpecificDisease', 'and-O', 'congenital-O', 'nystagmus-B-SpecificDisease', '(searching-O', 'gaze),-I-SpecificDisease', 'and-O', 'two-O', 'in-O', 'association-O', 'with-O', 'more-O', 'recognizable-O', 'aniridia-B-Modifier', 'phenotypes.-O']
['Strikingly,-O', 'all-O', 'four-O', 'mutations-O', 'are-O', 'located-O', 'within-O', 'the-O', 'PAX6-O', 'paired-O', 'domain-O', 'and-O', 'affect-O', 'amino-O', 'acids-O', 'which-O', 'are-O', 'highly-O', 'conserved-O', 'in-O', 'all-O', 'known-O', 'paired-O', 'domain-O', 'proteins.-O']
['Our-O', 'results-O', 'support-O', 'the-O', 'hypothesis-O', 'that-O', 'the-O', 'under-representation-O', 'of-O', 'missense-O', 'mutations-O', 'is-O', 'caused-O', 'by-O', 'ascertainment-O', 'bias-O', 'and-O', 'suggest-O', 'that-O', 'a-O', 'substantial-O', 'burden-O', 'of-O', 'PAX6-B-Modifier', '-related-O', 'disease-I-Modifier', 'remains-O', 'to-O', 'be-O', 'uncovered..-O']
['Severe-O', 'early-onset-O', 'obesity,-B-SpecificDisease', 'adrenal-B-DiseaseClass', 'insufficiency-I-DiseaseClass', 'and-O', 'red-O', 'hair-O', 'pigmentation-O', 'caused-O', 'by-O', 'POMC-O', 'mutations-O', 'in-O', 'humans.-O']
['Sequential-O', 'cleavage-O', 'of-O', 'the-O', 'precursor-O', 'protein-O', 'pre-pro-opiomelanocortin-O', '(POMC)-O', 'generates-O', 'the-O', 'melanocortin-O', 'peptides-O', 'adrenocorticotrophin-O', '(ACTH),-O', 'melanocyte-stimulating-O', 'hormones-O', '(MSH)-O', 'alpha,-O', 'beta-O', 'and-O', 'gamma-O', 'as-O', 'well-O', 'as-O', 'the-O', 'opioid-receptor-O', 'ligand-O', 'beta-endorphin.-O']
['While-O', 'a-O', 'few-O', 'cases-O', 'of-O', 'isolated-O', 'ACTH-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'have-O', 'been-O', 'reported-O', '(OMIM-O', '201400),-O', 'an-O', 'inherited-B-DiseaseClass', 'POMC-B-SpecificDisease', 'defect-I-SpecificDisease', 'has-O', 'not-O', 'been-O', 'described-O', 'so-O', 'far.-O']
['Recent-O', 'studies-O', 'in-O', 'animal-O', 'models-O', 'elucidated-O', 'a-O', 'central-O', 'role-O', 'of-O', 'alpha-MSH-O', 'in-O', 'the-O', 'regulation-O', 'of-O', 'food-O', 'intake-O', 'by-O', 'activation-O', 'of-O', 'the-O', 'brain-O', 'melanocortin-4-receptor-O', '(MC4-R;-O', 'refs-O', '3-5)-O', 'and-O', 'the-O', 'linkage-O', 'of-O', 'human-O', 'obesity-B-SpecificDisease', 'to-O', 'chromosome-O', '2-O', 'in-O', 'close-O', 'proximity-O', 'to-O', 'the-O', 'POMC-O', 'locus,-O', 'led-O', 'to-O', 'the-O', 'proposal-O', 'of-O', 'an-O', 'association-O', 'of-O', 'POMC-O', 'with-O', 'human-O', 'obesity.-O', 'The-O', 'dual-O', 'role-O', 'of-O', 'alpha-MSH-O', 'in-O', 'regulating-O', 'food-O', 'intake-O', 'and-O', 'influencing-O', 'hair-O', 'pigmentation-O', 'predicts-O', 'that-O', 'the-O', 'phenotype-O', 'associated-O', 'with-O', 'a-O', 'defect-O', 'in-O', 'POMC-O', 'function-O', 'would-O', 'include-O', 'obesity,-B-SpecificDisease', 'alteration-O', 'in-O', 'pigmentation-O', 'and-O', 'ACTH-O', 'deficiency.-O', 'The-O', 'observation-O', 'of-O', 'these-O', 'symptoms-O', 'in-O', 'two-O', 'probands-O', 'prompted-O', 'us-O', 'to-O', 'search-O', 'for-O', 'mutations-O', 'within-O', 'their-O', 'POMC-O', 'genes.-O']
['Patient-O', '1-O', 'was-O', 'found-O', 'to-O', 'be-O', 'a-O', 'compound-O', 'heterozygote-O', 'for-O', 'two-O', 'mutations-O', 'in-O', 'exon-O', '3-O', '(G7013T,-O', 'C7133delta)-O', 'which-O', 'interfere-O', 'with-O', 'appropriate-O', 'synthesis-O', 'of-O', 'ACTH-O', 'and-O', 'alpha-MSH.-O']
['Patient-O', '2-O', 'was-O', 'homozygous-O', 'for-O', 'a-O', 'mutation-O', 'in-O', 'exon-O', '2-O', '(C3804A)-O', 'which-O', 'abolishes-O', 'POMC-O', 'translation.-O']
['These-O', 'findings-O', 'represent-O', 'the-O', 'first-O', 'examples-O', 'of-O', 'a-O', 'genetic-O', 'defect-I-DiseaseClass', 'within-O', 'the-O', 'POMC-B-SpecificDisease', 'gene-I-SpecificDisease', 'and-O', 'define-O', 'a-O', 'new-O', 'monogenic-B-DiseaseClass', 'endocrine-B-DiseaseClass', 'disorder-I-DiseaseClass', 'resulting-O', 'in-O', 'early-onset-B-DiseaseClass', 'obesity,-I-DiseaseClass', 'adrenal-B-DiseaseClass', 'insufficiency-I-DiseaseClass', 'and-O', 'red-O', 'hair-O', 'pigmentation..-I-DiseaseClass']
['Genotype-phenotype-O', 'correlations-O', 'in-O', 'attenuated-O', 'adenomatous-B-SpecificDisease', 'polyposis-I-SpecificDisease', 'coli.-I-SpecificDisease', 'Germ-line-O', 'mutations-O', 'of-O', 'the-O', 'tumor-B-Modifier', 'suppressor-O', 'APC-B-Modifier', 'are-O', 'implicated-O', 'in-O', 'attenuated-O', 'adenomatous-B-SpecificDisease', 'polyposis-I-SpecificDisease', 'coli,-I-SpecificDisease', '(AAPC),-O', 'a-O', 'variant-O', 'of-O', 'familial-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', '(FAP).-O', 'AAPC-O', 'is-O', 'recognized-O', 'by-O', 'the-O', 'occurrence-O', 'of-O', '<-O', '100-O', 'colonic-O', 'adenomas-O', 'and-O', 'a-O', 'later-O', 'onset-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', '(age-O', '>-O', '40-O', 'years).-O', 'The-O', 'aim-O', 'of-O', 'this-O', 'study-O', 'was-O', 'to-O', 'assess-O', 'genotype-phenotype-O', 'correlations-O', 'in-O', 'AAPC-O', 'families.-O']
['By-O', 'protein-truncation-O', 'test-O', '(PTT)-O', 'assay,-O', 'the-O', 'entire-O', 'coding-O', 'region-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'was-O', 'screened-O', 'in-O', 'affected-O', 'individuals-O', 'from-O', '11-O', 'AAPC-B-Modifier', 'kindreds,-O', 'and-O', 'their-O', 'phenotypic-O', 'differences-O', 'were-O', 'examined.-O']
['Five-O', 'novel-O', 'germ-line-O', 'APC-B-Modifier', 'mutations-O', 'were-O', 'identified-O', 'in-O', 'seven-O', 'kindreds-O']
['Mutations-O', 'were-O', 'located-O', 'in-O', 'three-O', 'different-O', 'regions-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', '(1)-O', 'at-O', 'the-O', '5-O', 'end-O', 'spanning-O', 'exons-O', '4-O', 'and-O', '5,-O', '(2)-O', 'within-O', 'exon-O', '9,-O', 'and-O', '(3)-O', 'at-O', 'the-O', '3-O', 'distal-O', 'end-O', 'of-O', 'the-O', 'gene.-O']
['Variability-O', 'in-O', 'the-O', 'number-O', 'of-O', 'colorectal-B-SpecificDisease', 'adenomas-I-SpecificDisease', 'was-O', 'most-O', 'apparent-O', 'in-O', 'individuals-O', 'with-O', 'mutations-O', 'in-O', 'region-O', '1,-O', 'and-O', 'upper-gastrointestinal-O', 'manifestations-O', 'were-O', 'more-O', 'severe-O', 'in-O', 'them.-O']
['In-O', 'individuals-O', 'with-O', 'mutations-O', 'in-O', 'either-O', 'region-O', '2-O', 'or-O', 'region-O', '3,-O', 'the-O', 'average-O', 'number-O', 'of-O', 'adenomas-B-DiseaseClass', 'tended-O', 'to-O', 'be-O', 'lower-O', 'than-O', 'those-O', 'in-O', 'individuals-O', 'with-O', 'mutations-O', 'in-O', 'region-O', '1,-O', 'although-O', 'age-O', 'at-O', 'diagnosis-O', 'was-O', 'similar.-O']
['In-O', 'all-O', 'AAPC-B-SpecificDisease', 'kindreds,-O', 'a-O', 'predominance-O', 'of-O', 'right-sided-O', 'colorectal-B-SpecificDisease', 'adenomas-I-SpecificDisease', 'and-O', 'rectal-O', 'polyp-O', 'sparing-O', 'was-O', 'observed.-O']
['No-O', 'desmoid-B-DiseaseClass', 'tumors-I-DiseaseClass', 'were-O', 'found-O', 'in-O', 'these-O', 'kindreds.-O']
['Our-O', 'data-O', 'suggest-O', 'that,-O', 'in-O', 'AAPC-B-SpecificDisease', 'families,-O', 'the-O', 'location-O', 'of-O', 'the-O', 'APC-B-SpecificDisease', 'mutation-O', 'may-O', 'partially-O', 'predict-O', 'specific-O', 'phenotypic-O', 'expression.-O']
['This-O', 'should-O', 'help-O', 'in-O', 'the-O', 'design-O', 'of-O', 'tailored-O', 'clinical-management-O', 'protocols-O', 'in-O', 'this-O', 'subset-O', 'of-O', 'FAP-B-Modifier', 'patients..-O']
['Mutations-O', 'of-O', 'the-O', 'ATM-O', 'gene-O', 'detected-O', 'in-O', 'Japanese-O', 'ataxia-telangiectasia-B-SpecificDisease', 'patients:-O', 'possible-O', 'preponderance-O', 'of-O', 'the-O', 'two-O', 'founder-O', 'mutations-O', '4612del165-O', 'and-O', '7883del5.-O']
['The-O', 'ATM-O', '(A-T,-O', 'mutated)-O', 'gene-O', 'on-O', 'human-O', 'chromosome-O', '11q22.-O']
['3-O', 'has-O', 'recently-O', 'been-O', 'identified-O', 'as-O', 'the-O', 'gene-O', 'responsible-O', 'for-O', 'the-O', 'human-O', 'recessive-O', 'disease-O', 'ataxia-telangiectasia-B-SpecificDisease', '(A-T).-O', 'In-O', 'order-O', 'to-O', 'define-O', 'the-O', 'types-O', 'of-O', 'disease-causing-O', 'ATM-O', 'mutations-O', 'in-O', 'Japanese-O', 'A-T-B-SpecificDisease', 'patients-O', 'as-O', 'well-O', 'as-O', 'to-O', 'look-O', 'for-O', 'possible-O', 'mutational-O', 'hotspots,-O', 'reverse-transcribed-O', 'RNA-O', 'derived-O', 'from-O', 'ten-O', 'patients-O', 'belonging-O', 'to-O', 'eight-O', 'unrelated-O', 'Japanese-O', 'A-T-B-SpecificDisease', 'families-O', 'was-O', 'analyzed-O', 'for-O', 'mutations-O', 'by-O', 'the-O', 'restriction-O', 'endonuclease-O', 'fingerprinting-O', 'method.-O']
['As-O', 'has-O', 'been-O', 'reported-O', 'by-O', 'others,-O', 'mutations-O', 'that-O', 'lead-O', 'to-O', 'exon-O', 'skipping-O', 'or-O', 'premature-O', 'protein-O', 'truncation-O', 'were-O', 'also-O', 'predominant-O', 'in-O', 'our-O', 'mutants.-O']
['Six-O', 'different-O', 'mutations-O', 'were-O', 'identified-O', 'on-O', '12-O', 'of-O', 'the-O', '16-O', 'alleles-O', 'examined.-O']
['Four-O', 'were-O', 'deletions-O', 'involving-O', 'a-O', 'loss-O', 'of-O', 'a-O', 'single-O', 'exon-O', 'exon-O', '7,-O', 'exon-O', '16,-O', 'exon-O', '33-O', 'or-O', 'exon-O', '35.-O']
['The-O', 'others-O', 'were-O', 'minute-O', 'deletions,-O', '4649delA-O', 'in-O', 'exon-O', '33-O', 'and-O', '7883del5-O', 'in-O', 'exon-O', '55.-O']
['The-O', 'mutations-O', '4612del165-O', 'and-O', '7883del5-O', 'were-O', 'found-O', 'in-O', 'more-O', 'than-O', 'two-O', 'unrelated-O', 'families;-O', '44%-O', '(7-O', 'of-O', '16)-O', 'of-O', 'the-O', 'mutant-O', 'alleles-O', 'had-O', 'one-O', 'of-O', 'the-O', 'two-O', 'mutations.-O']
['The-O', '4612del165-O', 'mutations-O', 'in-O', 'three-O', 'different-O', 'families-O', 'were-O', 'all-O', 'ascribed-O', 'to-O', 'the-O', 'same-O', 'T--O', '>-O', 'A-O', 'substitution-O', 'at-O', 'the-O', 'splice-O', 'donor-O', 'site-O', 'in-O', 'intron-O', '33.-O']
['Microsatellite-O', 'genotyping-O', 'around-O', 'the-O', 'ATM-O', 'locus-O', 'also-O', 'indicated-O', 'that-O', 'a-O', 'common-O', 'haplotype-O', 'was-O', 'shared-O', 'by-O', 'the-O', 'mutant-O', 'alleles-O', 'in-O', 'both-O', 'mutations.-O']
['This-O', 'suggests-O', 'that-O', 'these-O', 'two-O', 'founder-O', 'mutations-O', 'may-O', 'be-O', 'predominant-O', 'among-O', 'Japanese-O', 'ATM-O', 'mutant-O', 'alleles.-O']
['Down-regulation-O', 'of-O', 'transmembrane-O', 'carbonic-O', 'anhydrases-O', 'in-O', 'renal-B-SpecificDisease', 'cell-I-SpecificDisease', 'carcinoma-I-SpecificDisease', 'cell-O', 'lines-O', 'by-O', 'wild-type-O', 'von-B-Modifier', 'Hippel-Lindau-I-Modifier', 'transgenes.-O']
['To-O', 'discover-O', 'genes-O', 'involved-O', 'in-O', 'von-B-SpecificDisease', 'Hippel-Lindau-I-SpecificDisease', '(VHL)-O', '-mediated-O', 'carcinogenesis,-O', 'we-O', 'used-O', 'renal-B-SpecificDisease', 'cell-I-SpecificDisease', 'carcinoma-I-SpecificDisease', 'cell-O', 'lines-O', 'stably-O', 'transfected-O', 'with-O', 'wild-type-O', 'VHL-expressing-O', 'transgenes.-O']
['Large-scale-O', 'RNA-O', 'differential-O', 'display-O', 'technology-O', 'applied-O', 'to-O', 'these-O', 'cell-O', 'lines-O', 'identified-O', 'several-O', 'differentially-O', 'expressed-O', 'genes,-O', 'including-O', 'an-O', 'alpha-O', 'carbonic-O', 'anhydrase-O', 'gene,-O', 'termed-O', 'CA12.-O']
['The-O', 'deduced-O', 'protein-O', 'sequence-O', 'was-O', 'classified-O', 'as-O', 'a-O', 'one-pass-O', 'transmembrane-O', 'CA-O', 'possessing-O', 'an-O', 'apparently-O', 'intact-O', 'catalytic-O', 'domain-O', 'in-O', 'the-O', 'extracellular-O', 'CA-O', 'module.-O']
['Reintroduced-O', 'wild-type-O', 'VHL-B-Modifier', 'strongly-O', 'inhibited-O', 'the-O', 'overexpression-O', 'of-O', 'the-O', 'CA12-O', 'gene-O', 'in-O', 'the-O', 'parental-O', 'renal-B-SpecificDisease', 'cell-I-SpecificDisease', 'carcinoma-I-SpecificDisease', 'cell-O', 'lines.-O']
['Similar-O', 'results-O', 'were-O', 'obtained-O', 'with-O', 'CA9,-O', 'encoding-O', 'another-O', 'transmembrane-O', 'CA-O', 'with-O', 'an-O', 'intact-O', 'catalytic-O', 'domain.-O']
['Although-O', 'both-O', 'domains-O', 'of-O', 'the-O', 'VHL-B-Modifier', 'protein-O', 'contribute-O', 'to-O', 'regulation-O', 'of-O', 'CA12-O', 'expression,-O', 'the-O', 'elongin-O', 'binding-O', 'domain-O', 'alone-O', 'could-O', 'effectively-O', 'regulate-O', 'CA9-O', 'expression.-O']
['We-O', 'mapped-O', 'CA12-O', 'and-O', 'CA9-O', 'loci-O', 'to-O', 'chromosome-O', 'bands-O', '15q22-O', 'and-O', '17q21.-O']
['2-O', 'respectively,-O', 'regions-O', 'prone-O', 'to-O', 'amplification-O', 'in-O', 'some-O', 'human-O', 'cancers.-B-DiseaseClass', 'Additional-O', 'experiments-O', 'are-O', 'needed-O', 'to-O', 'define-O', 'the-O', 'role-O', 'of-O', 'CA-O', 'IX-O', 'and-O', 'CA-O', 'XII-O', 'enzymes-O', 'in-O', 'the-O', 'regulation-O', 'of-O', 'pH-O', 'in-O', 'the-O', 'extracellular-O', 'microenvironment-O', 'and-O', 'its-O', 'potential-O', 'impact-O', 'on-O', 'cancer-B-DiseaseClass', 'cell-O', 'growth.-O']
['PAX6-O', 'mutations-O', 'reviewed.-O']
['Mutations-O', 'in-O', 'PAX6-O', 'are-O', 'responsible-O', 'for-O', 'human-O', 'aniridia-B-SpecificDisease', 'and-O', 'have-O', 'also-O', 'been-O', 'found-O', 'in-O', 'patients-O', 'with-O', 'Peters-B-SpecificDisease', 'anomaly,-I-SpecificDisease', 'with-O', 'congenital-B-SpecificDisease', 'cataracts,-I-SpecificDisease', 'with-O', 'autosomal-O', 'dominant-O', 'keratitis,-I-SpecificDisease', 'and-O', 'with-O', 'isolated-O', 'foveal-B-SpecificDisease', 'hypoplasia.-I-SpecificDisease', 'No-O', 'locus-O', 'other-O', 'than-O', 'chromosome-O', '11p13-O', 'has-O', 'been-O', 'implicated-O', 'in-O', 'aniridia,-B-SpecificDisease', 'and-O', 'PAX6-O', 'is-O', 'clearly-O', 'the-O', 'major,-O', 'if-O', 'not-O', 'only,-O', 'gene-O', 'responsible.-O']
['Twenty-eight-O', 'percent-O', 'of-O', 'identified-O', 'PAX6-O', 'mutations-O', 'are-O', 'C-T-O', 'changes-O', 'at-O', 'CpG-O', 'dinucleotides,-O', '20%-O', 'are-O', 'splicing-O', 'errors,-O', 'and-O', 'more-O', 'than-O', '30%-O', 'are-O', 'deletion-O', 'or-O', 'insertion-O', 'events.-O']
['There-O', 'is-O', 'a-O', 'noticeably-O', 'elevated-O', 'level-O', 'of-O', 'mutation-O', 'in-O', 'the-O', 'paired-O', 'domain-O', 'compared-O', 'with-O', 'the-O', 'rest-O', 'of-O', 'the-O', 'gene.-O']
['Increased-O', 'mutation-O', 'in-O', 'the-O', 'homeodomain-O', 'is-O', 'accounted-O', 'for-O', 'by-O', 'the-O', 'hypermutable-O', 'CpG-O', 'dinucleotide-O', 'in-O', 'codon-O', '240.-O']
['Very-O', 'nearly-O', 'all-O', 'mutations-O', 'appear-O', 'to-O', 'cause-O', 'loss-O', 'of-O', 'function-O', 'of-O', 'the-O', 'mutant-O', 'allele,-O', 'and-O', 'more-O', 'than-O', '80%-O', 'of-O', 'exonic-O', 'substitutions-O', 'result-O', 'in-O', 'nonsense-O', 'codons.-O']
['In-O', 'a-O', 'gene-O', 'with-O', 'such-O', 'extraordinarily-O', 'high-O', 'sequence-O', 'conservation-O', 'throughout-O', 'evolution,-O', 'there-O', 'are-O', 'presumed-O', 'undiscovered-O', 'missense-O', 'mutations,-O', 'these-O', 'are-O', 'hypothesized-O', 'to-O', 'exist-O', 'in-O', 'as-yet-O', 'unidentified-O', 'phenotypes..-O']
['Insertional-O', 'mutation-O', 'by-O', 'transposable-O', 'element,-O', 'L1,-O', 'in-O', 'the-O', 'DMD-B-Modifier', 'gene-O', 'results-O', 'in-O', 'X-linked-B-SpecificDisease', 'dilated-I-SpecificDisease', 'cardiomyopathy.-I-SpecificDisease', 'X-linked-B-SpecificDisease', 'dilated-I-SpecificDisease', 'cardiomyopathy-I-SpecificDisease', '(XLDCM)-O', 'is-O', 'a-O', 'clinical-O', 'phenotype-O', 'of-O', 'dystrophinopathy-O', 'which-O', 'is-O', 'characterized-O', 'by-O', 'preferential-O', 'myocardial-O', 'involvement-O', 'without-O', 'any-O', 'overt-O', 'clinical-O', 'signs-O', 'of-O', 'skeletal-O', 'myopathy.-O', 'To-O', 'date,-O', 'several-O', 'mutations-O', 'in-O', 'the-O', 'Duchenne-B-Modifier', 'muscular-I-Modifier', 'dystrophy-I-Modifier', 'gene,-O', 'DMD,-O', 'have-O', 'been-O', 'identified-O', 'in-O', 'patients-O', 'with-O', 'XLDCM,-B-SpecificDisease', 'but-O', 'a-O', 'pathogenic-O', 'correlation-O', 'of-O', 'these-O', 'cardiospecific-O', 'mutations-O', 'in-O', 'DMD-B-Modifier', 'with-O', 'the-O', 'XLDCM-B-SpecificDisease', 'phenotype-O', 'has-O', 'remained-O', 'to-O', 'be-O', 'elucidated.-O']
['We-O', 'report-O', 'here-O', 'the-O', 'identification-O', 'of-O', 'a-O', 'unique-O', 'de-O', 'novo-O', 'L1-O', 'insertion-O', 'in-O', 'the-O', 'muscle-O', 'exon-O', '1-O', 'in-O', 'DMD-B-SpecificDisease', 'in-O', 'three-O', 'XLDCM-O', 'patients-O', 'from-O', 'two-O', 'unrelated-O', 'Japanese-O', 'families.-O']
['The-O', 'insertion-O', 'was-O', 'a-O', '5-truncated-O', 'form-O', 'of-O', 'human-O', 'L1-O', 'inversely-O', 'integrated-O', 'in-O', 'the-O', '5-untranslated-O', 'region-O', 'in-O', 'the-O', 'muscle-O', 'exon-O', '1,-O', 'which-O', 'affected-O', 'the-O', 'transcription-O', 'or-O', 'the-O', 'stability-O', 'of-O', 'the-O', 'muscle-O', 'form-O', 'of-O', 'dystrophin-B-SpecificDisease', 'transcripts-O', 'but-O', 'not-O', 'that-O', 'of-O', 'the-O', 'brain-O', 'or-O', 'Purkinje-O', 'cell-O', 'form,-O', 'probably-O', 'due-O', 'to-O', 'its-O', 'unique-O', 'site-O', 'of-O', 'integration.-O']
['We-O', 'speculate-O', 'that-O', 'this-O', 'insertion-O', 'of-O', 'an-O', 'L1-O', 'sequence-O', 'in-O', 'DMD-B-Modifier', 'is-O', 'responsible-O', 'for-O', 'some-O', 'of-O', 'the-O', 'population-O', 'of-O', 'Japanese-O', 'patients-O', 'with-O', 'XLDCM-B-SpecificDisease..-O']
['Founder-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'mutations-O', 'in-O', 'French-O', 'Canadian-O', 'breast-B-CompositeMention', 'and-I-CompositeMention', 'ovarian-I-CompositeMention', 'cancer-I-CompositeMention', 'families.-O']
['We-O', 'have-O', 'identified-O', 'four-O', 'mutations-O', 'in-O', 'each-O', 'of-O', 'the-O', 'breast-B-Modifier', 'cancer-susceptibility-O', 'genes,-O', 'BRCA1-O', 'and-O', 'BRCA2,-O', 'in-O', 'French-O', 'Canadian-O', 'breast-B-CompositeMention', 'cancer-I-CompositeMention', 'and-O', 'breast/ovarian-I-CompositeMention', 'cancer-I-CompositeMention', 'families-O', 'from-O', 'Quebec.-O']
['To-O', 'identify-O', 'founder-O', 'effects,-O', 'we-O', 'examined-O', 'independently-O', 'ascertained-O', 'French-O', 'Canadian-O', 'cancer-B-Modifier', 'families-O', 'for-O', 'the-O', 'distribution-O', 'of-O', 'these-O', 'eight-O', 'mutations.-O']
['Mutations-O', 'were-O', 'found-O', 'in-O', '41-O', 'of-O', '97-O', 'families.-O']
['Six-O', 'of-O', 'eight-O', 'mutations-O', 'were-O', 'observed-O', 'at-O', 'least-O', 'twice.-O']
['The-O', 'BRCA1-O', 'C4446T-O', 'mutation-O', 'was-O', 'the-O', 'most-O', 'common-O', 'mutation-O', 'found,-O', 'followed-O', 'by-O', 'the-O', 'BRCA2-O', '8765delAG-O', 'mutation.-O']
['Together,-O', 'these-O', 'mutations-O', 'were-O', 'found-O', 'in-O', '28-O', 'of-O', '41-O', 'families-O', 'identified-O', 'to-O', 'have-O', 'a-O', 'mutation.-O']
['The-O', 'odds-O', 'of-O', 'detection-O', 'of-O', 'any-O', 'of-O', 'the-O', 'four-O', 'BRCA1-O', 'mutations-O', 'was-O', '18.-O']
['7x-O', 'greater-O', 'if-O', 'one-O', 'or-O', 'more-O', 'cases-O', 'of-O', 'ovarian-B-SpecificDisease', 'cancer-I-SpecificDisease', 'were-O', 'also-O', 'present-O', 'in-O', 'the-O', 'family.-O']
['The-O', 'odds-O', 'of-O', 'detection-O', 'of-O', 'any-O', 'of-O', 'the-O', 'four-O', 'BRCA2-O', 'mutations-O', 'was-O', '5.-O']
['3x-O', 'greater-O', 'if-O', 'there-O', 'were-O', 'at-O', 'least-O', 'five-O', 'cases-O', 'of-O', 'breast-B-SpecificDisease', 'cancer-I-SpecificDisease', 'in-O', 'the-O', 'family.-O']
['Interestingly,-O', 'the-O', 'presence-O', 'of-O', 'a-O', 'breast-B-SpecificDisease', 'cancer-I-SpecificDisease', 'case-O', '<-O', '36-O', 'years-O', 'of-O', 'age-O', 'was-O', 'strongly-O', 'predictive-O', 'of-O', 'the-O', 'presence-O', 'of-O', 'any-O', 'of-O', 'the-O', 'eight-O', 'mutations-O', 'screened.-O']
['Carriers-O', 'of-O', 'the-O', 'same-O', 'mutation,-O', 'from-O', 'different-O', 'families,-O', 'shared-O', 'similar-O', 'haplotypes,-O', 'indicating-O', 'that-O', 'the-O', 'mutant-O', 'alleles-O', 'were-O', 'likely-O', 'to-O', 'be-O', 'identical-O', 'by-O', 'descent-O', 'for-O', 'a-O', 'mutation-O', 'in-O', 'the-O', 'founder-O', 'population.-O']
['The-O', 'identification-O', 'of-O', 'common-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'mutations-O', 'will-O', 'facilitate-O', 'carrier-O', 'detection-O', 'in-O', 'French-O', 'Canadian-O', 'breast-B-CompositeMention', 'cancer-I-CompositeMention', 'and-O', 'breast/ovarian-I-CompositeMention', 'cancer-I-CompositeMention', 'families.-O']
['Mutation-O', 'analysis-O', 'of-O', 'UBE3A-O', 'in-O', 'Angelman-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'patients.-O']
['Angelman-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(AS)-O', 'is-O', 'caused-O', 'by-O', 'chromosome-O', '15q11-q13-O', 'deletions-O', 'of-O', 'maternal-O', 'origin,-O', 'by-O', 'paternal-O', 'uniparental-B-SpecificDisease', 'disomy-I-SpecificDisease', '(UPD)-O', '15,-O', 'by-O', 'imprinting-O', 'defects,-O', 'and-O', 'by-O', 'mutations-O', 'in-O', 'the-O', 'UBE3A-O', 'gene.-O']
['UBE3A-O', 'encodes-O', 'a-O', 'ubiquitin-protein-O', 'ligase-O', 'and-O', 'shows-O', 'brain-specific-O', 'imprinting.-O']
['Here-O', 'we-O', 'describe-O', 'UBE3A-O', 'coding-region-O', 'mutations-O', 'detected-O', 'by-O', 'SSCP-O', 'analysis-O', 'in-O', '13-O', 'AS-B-SpecificDisease', 'individuals-O', 'or-O', 'families.-O']
['Two-O', 'identical-O', 'de-O', 'novo-O', '5-bp-O', 'duplications-O', 'in-O', 'exon-O', '16-O', 'were-O', 'found.-O']
['Among-O', 'the-O', 'other-O', '11-O', 'unique-O', 'mutations,-O', '8-O', 'were-O', 'small-O', 'deletions-O', 'or-O', 'insertions-O', 'predicted-O', 'to-O', 'cause-O', 'frameshifts,-O', '1-O', 'was-O', 'a-O', 'mutation-O', 'to-O', 'a-O', 'stop-O', 'codon,-O', '1-O', 'was-O', 'a-O', 'missense-O', 'mutation,-O', 'and-O', '1-O', 'was-O', 'predicted-O', 'to-O', 'cause-O', 'insertion-O', 'of-O', 'an-O', 'isoleucine-O', 'in-O', 'the-O', 'hect-O', 'domain-O', 'of-O', 'the-O', 'UBE3A-O', 'protein,-O', 'which-O', 'functions-O', 'in-O', 'E2-O', 'binding-O', 'and-O', 'ubiquitin-O', 'transfer.-O']
['Eight-O', 'of-O', 'the-O', 'cases-O', 'were-O', 'familial,-B-Modifier', 'and-O', 'five-O', 'were-O', 'sporadic.-O']
['In-O', 'two-O', 'familial-O', 'cases-O', 'and-O', 'one-O', 'sporadic-O', 'case,-O', 'mosaicism-O', 'for-O', 'UBE3A-O', 'mutations-O', 'was-O', 'detected-O', 'in-O', 'the-O', 'mother-O', 'of-O', 'three-O', 'AS-B-SpecificDisease', 'sons,-O', 'in-O', 'the-O', 'maternal-O', 'grandfather-O', 'of-O', 'two-O', 'AS-B-SpecificDisease', 'first-O', 'cousins,-O', 'and-O', 'in-O', 'the-O', 'mother-O', 'of-O', 'an-O', 'AS-B-SpecificDisease', 'daughter.-O']
['The-O', 'frequencies-O', 'with-O', 'which-O', 'we-O', 'detected-O', 'mutations-O', 'were-O', '5-O', '(14%)-O', 'of-O', '35-O', 'in-O', 'sporadic-O', 'cases-O', 'and-O', '8-O', '(80%)-O', 'of-O', '10-O', 'in-O', 'familial-B-Modifier', 'cases..-O']
['ATM-O', 'germline-O', 'mutations-O', 'in-O', 'classical-O', 'ataxia-telangiectasia-B-SpecificDisease', 'patients-O', 'in-O', 'the-O', 'Dutch-O', 'population.-O']
['Germline-O', 'mutations-O', 'in-O', 'the-O', 'ATM-O', 'gene-O', 'are-O', 'responsible-O', 'for-O', 'the-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'disorder-I-DiseaseClass', 'ataxia-telangiectasia-B-SpecificDisease', '(A-T).-O', 'In-O', 'our-O', 'study,-O', 'we-O', 'have-O', 'determined-O', 'the-O', 'ATM-O', 'mutation-O', 'spectrum-O', 'in-O', '19-O', 'classical-O', 'A-T-B-Modifier', 'patients,-O', 'including-O', 'some-O', 'immigrant-O', 'populations,-O', 'as-O', 'well-O', 'as-O', '12-O', 'of-O', 'Dutch-O', 'ethnic-O', 'origin.-O']
['Both-O', 'the-O', 'protein-O', 'truncation-O', 'test-O', '(PTT)-O', 'and-O', 'the-O', 'restriction-O', 'endonuclease-O', 'fingerprinting-O', '(REF)-O', 'method-O', 'were-O', 'used-O', 'and-O', 'compared-O', 'for-O', 'their-O', 'detection-O', 'efficiency,-O', 'identifying-O', '76%-O', 'and-O', '60%-O', 'of-O', 'the-O', 'mutations,-O', 'respectively.-O']
['Most-O', 'patients-O', 'were-O', 'found-O', 'to-O', 'be-O', 'compound-O', 'heterozygote.-O']
['Seventeen-O', 'mutations-O', 'were-O', 'distinct,-O', 'of-O', 'which-O', '10-O', 'were-O', 'not-O', 'reported-O', 'previously.-O']
['Mutations-O', 'are-O', 'small-O', 'deletions-O', 'or-O', 'point-O', 'mutations-O', 'frequently-O', 'affecting-O', 'splice-O', 'sites.-O']
['Moreover,-O', 'a-O', '16.-O']
['7-kb-O', 'genomic-O', 'deletion-O', 'of-O', 'the-O', '3-O', 'end-O', 'of-O', 'the-O', 'gene,-O', 'most-O', 'likely-O', 'a-O', 'result-O', 'of-O', 'recombination-O', 'between-O', 'two-O', 'LINE-O', 'elements,-O', 'was-O', 'identified.-O']
['The-O', 'most-O', 'frequently-O', 'found-O', 'mutation,-O', 'identified-O', 'in-O', 'three-O', 'unrelated-O', 'Turkish-O', 'A-T-B-SpecificDisease', 'individuals,-O', 'was-O', 'previously-O', 'described-O', 'to-O', 'be-O', 'a-O', 'Turkish-O', 'A-T-B-SpecificDisease', 'founder-O', 'mutation.-O']
['The-O', 'presence-O', 'of-O', 'a-O', 'founder-O', 'mutation-O', 'among-O', 'relatively-O', 'small-O', 'ethnic-O', 'population-O', 'groups-O', 'in-O', 'Western-O', 'Europe-O', 'could-O', 'indicate-O', 'a-O', 'high-O', 'carrier-O', 'frequency-O', 'in-O', 'such-O', 'communities.-O']
['In-O', 'patients-O', 'of-O', 'Dutch-O', 'ethnic-O', 'origin,-O', 'however,-O', 'no-O', 'significant-O', 'founder-O', 'effect-O', 'could-O', 'be-O', 'identified.-O']
['The-O', 'observed-O', 'genetic-O', 'heterogeneity-O', 'including-O', 'the-O', 'relative-O', 'high-O', 'percentage-O', 'of-O', 'splice-site-O', 'mutations-O', 'had-O', 'no-O', 'reflection-O', 'on-O', 'the-O', 'phenotype.-O']
['All-O', 'patients-O', 'manifested-O', 'classical-B-SpecificDisease', 'A-T-B-SpecificDisease', 'and-O', 'increased-O', 'cellular-O', 'radioresistant-O', 'DNA-O', 'synthesis.-O']
['Genetic-O', 'heterogeneity-O', 'of-O', 'Saethre-Chotzen-B-SpecificDisease', 'syndrome,-I-SpecificDisease', 'due-O', 'to-O', 'TWIST-O', 'and-O', 'FGFR-O', 'mutations.-O']
['Thirty-two-O', 'unrelated-O', 'patients-O', 'with-O', 'features-O', 'of-O', 'Saethre-Chotzen-B-SpecificDisease', 'syndrome,-I-SpecificDisease', 'a-O', 'common-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'condition-I-DiseaseClass', 'of-O', 'craniosynostosis-B-Modifier', 'and-O', 'limb-B-Modifier', 'anomalies,-I-Modifier', 'were-O', 'screened-O', 'for-O', 'mutations-O', 'in-O', 'TWIST,-O', 'FGFR2,-O', 'and-O', 'FGFR3.-O']
['Nine-O', 'novel-O', 'and-O', 'three-O', 'recurrent-O', 'TWIST-B-Modifier', 'mutations-O', 'were-O', 'found-O', 'in-O', '12-O', 'families.-O']
['Seven-O', 'families-O', 'were-O', 'found-O', 'to-O', 'have-O', 'the-O', 'FGFR3-B-Modifier', 'P250R-O', 'mutation,-O', 'and-O', 'one-O', 'individual-O', 'was-O', 'found-O', 'to-O', 'have-O', 'an-O', 'FGFR2-B-Modifier', 'VV269-270-O', 'deletion.-O']
['To-O', 'date,-O', 'our-O', 'detection-O', 'rate-O', 'for-O', 'TWIST-O', 'or-O', 'FGFR-O', 'mutations-O', 'is-O', '68%-O', 'in-O', 'our-O', 'Saethre-Chotzen-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'patients,-O', 'including-O', 'our-O', 'five-O', 'patients-O', 'elsewhere-O', 'reported-O', 'with-O', 'TWIST-O', 'mutations.-O']
['More-O', 'than-O', '35-O', 'different-O', 'TWIST-B-Modifier', 'mutations-O', 'are-O', 'now-O', 'known-O', 'in-O', 'the-O', 'literature.-O']
['The-O', 'most-O', 'common-O', 'phenotypic-O', 'features,-O', 'present-O', 'in-O', 'more-O', 'than-O', 'a-O', 'third-O', 'of-O', 'our-O', 'patients-O', 'with-O', 'TWIST-B-Modifier', 'mutations,-O', 'are-O', 'coronal-O', 'synostosis,-O', 'brachycephaly,-O', 'low-O', 'frontal-O', 'hairline,-O', 'facial-O', 'asymmetry,-O', 'ptosis,-O', 'hypertelorism,-O', 'broad-O', 'great-O', 'toes,-O', 'and-O', 'clinodactyly.-O', 'Significant-O', 'intra--O', 'and-O', 'interfamilial-O', 'phenotypic-O', 'variability-O', 'is-O', 'present-O', 'for-O', 'either-O', 'TWIST-B-Modifier', 'mutations-O', 'or-O', 'FGFR-B-Modifier', 'mutations.-O']
['The-O', 'overlap-O', 'in-O', 'clinical-O', 'features-O', 'and-O', 'the-O', 'presence,-O', 'in-O', 'the-O', 'same-O', 'genes,-O', 'of-O', 'mutations-O', 'for-O', 'more-O', 'than-O', 'one-O', 'craniosynostotic-O', 'condition-such-O', 'as-O', 'Saethre-Chotzen,-B-SpecificDisease', 'Crouzon,-I-SpecificDisease', 'and-O', 'Pfeiffer-I-SpecificDisease', 'syndromes-O', 'support-O', 'the-O', 'hypothesis-O', 'that-O', 'TWIST-O', 'and-O', 'FGFRs-O', 'are-O', 'components-O', 'of-O', 'the-O', 'same-O', 'molecular-O', 'pathway-O', 'involved-O', 'in-O', 'the-O', 'modulation-O', 'of-O', 'craniofacial-O', 'and-O', 'limb-O', 'development-O', 'in-O', 'humans..-O']
['Truncation-O', 'mutations-O', 'in-O', 'the-O', 'transactivation-O', 'region-O', 'of-O', 'PAX6-O', 'result-O', 'in-O', 'dominant-negative-O', 'mutants.-O']
['PAX6-O', 'is-O', 'a-O', 'transcription-O', 'factor-O', 'with-O', 'two-O', 'DNA-binding-O', 'domains-O', '(paired-O', 'box-O', 'and-O', 'homeobox)-O', 'and-O', 'a-O', 'proline-serine-threonine-O', '(PST)-O', '-rich-O', 'transactivation-O', 'domain.-O']
['PAX6-O', 'regulates-O', 'eye-O', 'development-O', 'in-O', 'animals-O', 'ranging-O', 'from-O', 'jellyfish-O', 'to-O', 'Drosophila-O', 'to-O', 'humans.-O']
['Heterozygous-O', 'mutations-O', 'in-O', 'the-O', 'human-O', 'PAX6-O', 'gene-O', 'result-O', 'in-O', 'various-O', 'phenotypes,-O', 'including-O', 'aniridia,-B-SpecificDisease', 'Peters-B-SpecificDisease', 'anomaly,-I-SpecificDisease', 'autosomal-O', 'dominant-O', 'keratitis,-B-SpecificDisease', 'and-O', 'familial-O', 'foveal-O', 'dysplasia.-B-SpecificDisease', 'It-O', 'is-O', 'believed-O', 'that-O', 'the-O', 'mutated-O', 'allele-O', 'of-O', 'PAX6-O', 'produces-O', 'an-O', 'inactive-O', 'protein-O', 'and-O', 'aniridia-O', 'is-O', 'caused-O', 'due-O', 'to-O', 'genetic-O', 'haploinsufficiency.-O']
['However,-O', 'several-O', 'truncation-O', 'mutations-O', 'have-O', 'been-O', 'found-O', 'to-O', 'occur-O', 'in-O', 'the-O', 'C-terminal-O', 'half-O', 'of-O', 'PAX6-O', 'in-O', 'patients-O', 'with-O', 'Aniridia-B-SpecificDisease', 'resulting-O', 'in-O', 'mutant-O', 'proteins-O', 'that-O', 'retain-O', 'the-O', 'DNA-binding-O', 'domains-O', 'but-O', 'have-O', 'lost-O', 'most-O', 'of-O', 'the-O', 'transactivation-O', 'domain.-O']
['It-O', 'is-O', 'not-O', 'clear-O', 'whether-O', 'such-O', 'mutants-O', 'really-O', 'behave-O', 'as-O', 'loss-of-function-O', 'mutants-O', 'as-O', 'predicted-O', 'by-O', 'haploinsufficiency-O']
['Contrary-O', 'to-O', 'this-O', 'theory,-O', 'our-O', 'data-O', 'showed-O', 'that-O', 'these-O', 'mutants-O', 'are-O', 'dominant-negative-O', 'in-O', 'transient-O', 'transfection-O', 'assays-O', 'when-O', 'they-O', 'are-O', 'coexpressed-O', 'with-O', 'wild-type-O', 'PAX6.-O']
['We-O', 'found-O', 'that-O', 'the-O', 'dominant-negative-O', 'effects-O', 'result-O', 'from-O', 'the-O', 'enhanced-O', 'DNA-O', 'binding-O', 'ability-O', 'of-O', 'these-O', 'mutants.-O']
['Kinetic-O', 'studies-O', 'of-O', 'binding-O', 'and-O', 'dissociation-O', 'revealed-O', 'that-O', 'various-O', 'truncation-O', 'mutants-O', 'have-O', '3-5-fold-O', 'higher-O', 'affinity-O', 'to-O', 'various-O', 'DNA-binding-O', 'sites-O', 'when-O', 'compared-O', 'with-O', 'the-O', 'wild-type-O', 'PAX6.-O']
['These-O', 'results-O', 'provide-O', 'a-O', 'new-O', 'insight-O', 'into-O', 'the-O', 'role-O', 'of-O', 'mutant-O', 'PAX6-O', 'in-O', 'causing-O', 'aniridia..-B-SpecificDisease']
['Mutation-O', 'spectrum-O', 'and-O', 'genotype-phenotype-O', 'analyses-O', 'in-O', 'Cowden-B-SpecificDisease', 'disease-I-SpecificDisease', 'and-O', 'Bannayan-Zonana-I-SpecificDisease', 'syndrome,-O', 'two-O', 'hamartoma-O', 'syndromes-O', 'with-O', 'germline-O', 'PTEN-O', 'mutation.-O']
['The-O', 'tumour-B-Modifier', 'suppressor-O', 'gene-O', 'PTEN,-O', 'which-O', 'maps-O', 'to-O', '10q23.-O']
['3-O', 'and-O', 'encodes-O', 'a-O', '403-O', 'amino-O', 'acid-O', 'dual-O', 'specificity-O', 'phosphatase-O', '(protein-O', 'tyrosine-O', 'phosphatase;-O', 'PTPase),-O', 'was-O', 'shown-O', 'recently-O', 'to-O', 'play-O', 'a-O', 'broad-O', 'role-O', 'in-O', 'human-O', 'malignancy.-O', 'Somatic-O', 'PTEN-B-Modifier', 'deletions-O', 'and-O', 'mutations-O', 'were-O', 'observed-O', 'in-O', 'sporadic-B-SpecificDisease', 'breast-I-SpecificDisease', 'brain-I-SpecificDisease', 'prostate-I-SpecificDisease', 'and-O', 'kidney-I-SpecificDisease', 'cancer-I-SpecificDisease', 'cell-O', 'lines-O', 'and-O', 'in-O', 'several-O', 'primary-O', 'tumours-O', 'such-O', 'as-O', 'endometrial-B-SpecificDisease', 'carcinomas,-I-SpecificDisease', 'malignant-O', 'melanoma-O', 'and-O', 'thyroid-O', 'tumours.-O', 'In-O', 'addition,-O', 'PTEN-B-Modifier', 'was-O', 'identified-O', 'as-O', 'the-O', 'susceptibility-O', 'gene-O', 'for-O', 'two-O', 'hamartoma-O', 'syndromes-O', 'Cowden-O', 'disease-O', '(CD;-O', 'MIM-O', '158350)-O', 'and-O', 'Bannayan-Zonana-O', '(BZS)-O', 'or-O', 'Ruvalcaba-Riley-Smith-O', 'syndrome-O', '(MIM-O', '153480).-O', 'Constitutive-O', 'DNA-O', 'from-O', '37-O', 'CD-O', 'families-O', 'and-O', 'seven-O', 'BZS-O', 'families-O', 'was-O', 'screened-O', 'for-O', 'germline-O', 'PTEN-O', 'mutations.-O']
['PTEN-O', 'mutations-O', 'were-O', 'identified-O', 'in-O', '30-O', 'of-O', '37-O', '(81%)-O', 'CD-B-Modifier', 'families,-O', 'including-O', 'missense-O', 'and-O', 'nonsense-O', 'point-O', 'mutations,-O', 'deletions,-O', 'insertions,-O', 'a-O', 'deletion/insertion-O', 'and-O', 'splice-O', 'site-O', 'mutations.-O']
['These-O', 'mutations-O', 'were-O', 'scattered-O', 'over-O', 'the-O', 'entire-O', 'length-O', 'of-O', 'PTEN,-O', 'with-O', 'the-O', 'exception-O', 'of-O', 'the-O', 'first,-O', 'fourth-O', 'and-O', 'last-O', 'exons.-O']
['A-O', 'hot-O', 'spot-O', 'for-O', 'PTEN-B-Modifier', 'mutation-O', 'in-O', 'CD-B-DiseaseClass', 'was-O', 'identified-O', 'in-O', 'exon-O', '5-O', 'that-O', 'contains-O', 'the-O', 'PTPase-O', 'core-O', 'motif,-O', 'with-O', '13-O', 'of-O', '30-O', '(43%)-O', 'CD-B-DiseaseClass', 'mutations-O', 'identified-O', 'in-O', 'this-O', 'exon.-O']
['Seven-O', 'of-O', '30-O', '(23%)-O', 'were-O', 'within-O', 'the-O', 'core-O', 'motif,-O', 'the-O', 'majority-O', '(five-O', 'of-O', 'seven)-O', 'of-O', 'which-O', 'were-O', 'missense-O', 'mutations,-O', 'possibly-O', 'pointing-O', 'to-O', 'the-O', 'functional-O', 'significance-O', 'of-O', 'this-O', 'region.-O']
['Germline-O', 'PTEN-B-Modifier', 'mutations-O', 'were-O', 'identified-O', 'in-O', 'four-O', 'of-O', 'seven-O', '(57%)-O', 'BZS-B-Modifier', 'families-O', 'studied.-O']
['Interestingly,-O', 'none-O', 'of-O', 'these-O', 'mutations-O', 'was-O', 'observed-O', 'in-O', 'the-O', 'PTPase-B-Modifier', 'core-O', 'motif.-O']
['It-O', 'is-O', 'also-O', 'worthy-O', 'of-O', 'note-O', 'that-O', 'a-O', 'single-O', 'nonsense-O', 'point-O', 'mutation,-O', 'R233X,-O', 'was-O', 'observed-O', 'in-O', 'the-O', 'germline-O', 'DNA-O', 'from-O', 'two-O', 'unrelated-O', 'CD-B-Modifier', 'families-O', 'and-O', 'one-O', 'BZS-B-Modifier', 'family.-O']
['Genotype-phenotype-O', 'studies-O', 'were-O', 'not-O', 'performed-O', 'on-O', 'this-O', 'small-O', 'group-O', 'of-O', 'BZS-B-SpecificDisease', 'families.-O']
['However,-O', 'genotype-phenotype-O', 'analysis-O', 'in-O', 'the-O', 'group-O', 'of-O', 'CD-B-Modifier', 'families-O', 'revealed-O', 'two-O', 'possible-O', 'associations-O', 'worthy-O', 'of-O', 'follow-up-O', 'in-O', 'independent-O', 'analyses.-O']
['The-O', 'first-O', 'was-O', 'an-O', 'association-O', 'noted-O', 'in-O', 'the-O', 'group-O', 'of-O', 'CD-B-Modifier', 'families-O', 'with-O', 'breast-B-CompositeMention', 'disease.-O', 'A-O', 'correlation-O', 'was-O', 'observed-O', 'between-O', 'the-O', 'presence/absence-O', 'of-O', 'a-O', 'PTEN-B-Modifier', 'mutation-O', 'and-O', 'the-O', 'type-O', 'of-O', 'breast-I-CompositeMention', 'involvement-O', '(unaffected-O', 'versus-O', 'benign-O', 'versus-O', 'malignant).-O', 'Specifically-O', 'and-O', 'more-O', 'directly,-O', 'an-O', 'association-O', 'was-O', 'also-O', 'observed-O', 'between-O', 'the-O', 'presence-O', 'of-O', 'a-O', 'PTEN-B-Modifier', 'mutation-O', 'and-O', 'malignant-B-SpecificDisease', 'breast-I-SpecificDisease', 'disease.-I-SpecificDisease', 'Secondly,-O', 'there-O', 'appeared-O', 'to-O', 'be-O', 'an-O', 'interdependent-O', 'association-O', 'between-O', 'mutations-O', 'upstream-O', 'and-O', 'within-O', 'the-O', 'PTPase-O', 'core-O', 'motif,-O', 'the-O', 'core-O', 'motif-O', 'containing-O', 'the-O', 'majority-O', 'of-O', 'missense-O', 'mutations,-O', 'and-O', 'the-O', 'involvement-O', 'of-O', 'all-O', 'major-O', 'organ-O', 'systems-O', '(central-O', 'nervous-O', 'system,-O', 'thyroid,-O', 'breast,-O', 'skin-O', 'and-O', 'gastrointestinal-O', 'tract).-O', 'However,-O', 'these-O', 'observations-O', 'would-O', 'need-O', 'to-O', 'be-O', 'confirmed-O', 'by-O', 'studying-O', 'a-O', 'larger-O', 'number-O', 'of-O', 'CD-B-Modifier', 'families.-O']
['Localization-O', 'of-O', 'human-O', 'BRCA1-O', 'and-O', 'its-O', 'loss-O', 'in-O', 'high-grade,-O', 'non-inherited-O', 'breast-B-SpecificDisease', 'carcinomas.-I-SpecificDisease', 'Although-O', 'the-O', 'link-O', 'between-O', 'the-O', 'BRCA1-O', 'tumour-suppressor-O', 'gene-O', 'and-O', 'hereditary-B-CompositeMention', 'breast-I-CompositeMention', 'and-I-CompositeMention', 'ovarian-I-CompositeMention', 'cancer-I-CompositeMention', 'is-O', 'established,-O', 'the-O', 'role,-O', 'if-O', 'any,-O', 'of-O', 'BRCA1-O', 'in-O', 'non-familial-O', 'cancers-O', 'is-O', 'unclear.-O']
['BRCA1-O', 'mutations-O', 'are-O', 'rare-O', 'in-O', 'sporadic-O', 'cancers,-O', 'but-O', 'loss-O', 'of-O', 'BRCA1-O', 'resulting-O', 'from-O', 'reduced-O', 'expression-O', 'or-O', 'incorrect-O', 'subcellular-O', 'localization-O', 'is-O', 'postulated-O', 'to-O', 'be-O', 'important-O', 'in-O', 'non-familial-O', 'breast-B-SpecificDisease', 'and-O', 'ovarian-I-SpecificDisease', 'cancers.-O', 'Epigenetic-O', 'loss,-O', 'however,-O', 'has-O', 'not-O', 'received-O', 'general-O', 'acceptance-O', 'due-O', 'to-O', 'controversy-O', 'regarding-O', 'the-O', 'subcellular-O', 'localization-O', 'of-O', 'BRCA1-O', 'proteins,-O', 'reports-O', 'of-O', 'which-O', 'have-O', 'ranged-O', 'from-O', 'exclusively-O', 'nuclear,-O', 'to-O', 'conditionally-O', 'nuclear,-O', 'to-O', 'the-O', 'ER/golgi,-O', 'to-O', 'cytoplasmic-O', 'invaginations-O', 'into-O', 'the-O', 'nucleus.-O']
['In-O', 'an-O', 'attempt-O', 'to-O', 'resolve-O', 'this-O', 'issue,-O', 'we-O', 'have-O', 'comprehensively-O', 'characterized-O', '19-O', 'anti-BRCA1-O', 'antibodies.-O']
['These-O', 'reagents-O', 'detect-O', 'a-O', '220-kD-O', 'protein-O', 'localized-O', 'in-O', 'discrete-O', 'nuclear-O', 'foci-O', 'in-O', 'all-O', 'epithelial-O', 'cell-O', 'lines,-O', 'including-O', 'those-O', 'derived-O', 'from-O', 'breast-B-SpecificDisease', 'malignancies.-O', 'Immunohistochemical-O', 'staining-O', 'of-O', 'human-O', 'breast-B-SpecificDisease', 'specimens-O', 'also-O', 'revealed-O', 'BRCA1-O', 'nuclear-O', 'foci-O', 'in-O', 'benign-O', 'breast,-O', 'invasive-O', 'lobular-O', 'cancers-O', 'and-O', 'low-grade-O', 'ductal-O', 'carcinomas.-O', 'Conversely,-O', 'BRCA1-O', 'expression-O', 'was-O', 'reduced-O', 'or-O', 'undetectable-O', 'in-O', 'the-O', 'majority-O', 'of-O', 'high-grade,-O', 'ductal-O', 'carcinomas,-O', 'suggesting-O', 'that-O', 'absence-O', 'of-O', 'BRCA1-O', 'may-O', 'contribute-O', 'to-O', 'the-O', 'pathogenesis-O', 'of-O', 'a-O', 'significant-O', 'percentage-O', 'of-O', 'sporadic-B-SpecificDisease', 'breast-I-SpecificDisease', 'cancers..-I-SpecificDisease']
['Identification-O', 'of-O', 'a-O', 'novel-O', 'mutation-O', 'of-O', 'the-O', 'CPO-O', 'gene-O', 'in-O', 'a-O', 'Japanese-O', 'hereditary-O', 'coproporphyria-B-SpecificDisease', 'family.-I-SpecificDisease']
['Hereditary-B-SpecificDisease', 'coproporphyria-I-SpecificDisease', '(HCP)-O', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'disease-I-DiseaseClass', 'characterized-O', 'by-O', 'a-O', 'deficiency-B-SpecificDisease', 'of-I-SpecificDisease', 'coproporphyrinogen-I-SpecificDisease', 'oxidase-I-SpecificDisease', '(CPO)-I-SpecificDisease', 'caused-O', 'by-O', 'a-O', 'mutation-O', 'in-O', 'the-O', 'CPO-O', 'gene.-O']
['Only-O', '11-O', 'mutations-O', 'of-O', 'the-O', 'gene-O', 'have-O', 'been-O', 'reported-O', 'in-O', 'HCP-B-SpecificDisease', 'patients.-O']
['We-O', 'report-O', 'another-O', 'mutation-O', 'in-O', 'a-O', 'Japanese-O', 'family.-O']
['Polymerase-O', 'chain-O', 'reaction-single-O', 'strand-O', 'conformational-O', 'polymorphism-O', 'and-O', 'direct-O', 'sequence-O', 'analyses-O', 'demonstrated-O', 'a-O', 'C-O', 'to-O', 'T-O', 'substitution-O', 'in-O', 'exon-O', '1-O', 'of-O', 'the-O', 'CPO-O', 'gene-O', 'at-O', 'nucleotide-O', 'position-O', '85,-O', 'which-O', 'lies-O', 'in-O', 'the-O', 'putative-O', 'presequence-O', 'for-O', 'targeting-O', 'to-O', 'mitochondria.-O']
['This-O', 'mutation-O', 'changes-O', 'the-O', 'codon-O', 'for-O', 'glutamine-O', 'to-O', 'a-O', 'termination-O', 'codon-O', 'at-O', 'amino-O', 'acid-O', 'position-O', '29.-O']
['MaeI-O', 'restriction-O', 'analysis-O', 'showed-O', 'two-O', 'other-O', 'carriers-O', 'in-O', 'the-O', 'family.-O']
['The-O', 'C-T-O', 'mutation-O', 'is-O', 'located-O', 'within-O', 'a-O', 'recently-O', 'proposed-O', 'putative-O', 'alternative-O', 'translation-O', 'initiation-O', 'codon-O', '(TIC-1),-O', 'supporting-O', 'that-O', 'TIC-1-O', 'is-O', 'the-O', 'real-O', 'TIC-O', 'rather-O', 'than-O', 'TIC-2..-O']
['Ethnic-O', 'differences-O', 'in-O', 'the-O', 'HFE-O', 'codon-O', '282-O', '(Cys/Tyr)-O', 'polymorphism.-O']
['Recent-O', 'studies-O', 'have-O', 'shown-O', 'that-O', 'hereditary-B-SpecificDisease', 'hemochromatosis-I-SpecificDisease', '(HH)-O', 'is-O', 'likely-O', 'to-O', 'be-O', 'caused-O', 'by-O', 'homozygosity-O', 'for-O', 'a-O', 'Cys282Tyr-O', 'mutation-O', 'in-O', 'the-O', 'HFE-B-SpecificDisease', 'gene-O', 'located-O', '4.-O']
['5-O', 'Mb-O', 'telomeric-O', 'to-O', 'HLA-A-O']
['Population-O', 'studies-O', 'of-O', 'this-O', 'polymorphism-O', 'are-O', 'facilitated-O', 'by-O', 'the-O', 'fact-O', 'that-O', 'the-O', 'Cys282Tyr-O', 'mutation-O', 'creates-O', 'a-O', 'Rsal-O', 'restriction-O', 'site.-O']
['We-O', 'have-O', 'studied-O', 'the-O', 'codon-O', '282-O', '(Cys/Tyr)-O', 'polymorphism-O', 'in-O', 'different-O', 'ethnic-O', 'groups.-O']
['In-O', 'agreement-O', 'with-O', 'previous-O', 'observations-O', 'the-O', 'Tyr-O', 'allele-O', 'appeared-O', 'to-O', 'be-O', 'rare-O', 'or-O', 'absent-O', 'in-O', 'Asiatic-O', '(Indian,-O', 'Chinese)-O', 'populations.-O']
['The-O', 'highest-O', 'allele-O', 'frequency-O', '(7.-O']
['5%)-O', 'was-O', 'found-O', 'in-O', 'Swedes.-O']
['Saamis-O', '(2%)-O', 'and-O', 'Mordvinians-O', '(1.-O']
['8%)-O', 'had-O', 'significantly-O', 'lower-O', 'frequencies-O', 'of-O', 'the-O', 'Tyr-O', 'allele.-O']
['Comparisons-O', 'with-O', 'allele-O', 'frequencies-O', 'based-O', 'on-O', 'prevalence-O', 'estimates-O', 'of-O', 'HH-B-Modifier', 'showed-O', 'some-O', 'disagreements-O', 'with-O', 'the-O', 'RFLP-O', 'data,-O', 'particularly-O', 'in-O', 'Finns.-O']
['The-O', 'newly-O', 'described-O', 'HFE-O', 'marker-O', 'provides-O', 'a-O', 'new-O', 'approach-O', 'to-O', 'the-O', 'screening-O', 'of-O', 'HH-B-SpecificDisease', 'as-O', 'well-O', 'as-O', 'studies-O', 'of-O', 'the-O', 'relationship-O', 'between-O', 'the-O', 'HFE-O', 'Tyr-O', 'allele-O', 'and-O', 'different-O', 'disorders-O', 'including-O', 'cancer-B-DiseaseClass']
['A-O', 'novel-O', 'Arg362Ser-O', 'mutation-O', 'in-O', 'the-O', 'sterol-O', '27-hydroxylase-O', 'gene-O', '(CYP27):-O', 'its-O', 'effects-O', 'on-O', 'pre-mRNA-O', 'splicing-O', 'and-O', 'enzyme-O', 'activity.-O']
['A-O', 'novel-O', 'C-O', 'to-O', 'A-O', 'mutation-O', 'in-O', 'the-O', 'sterol-O', '27-hydroxylase-O', 'gene-O', '(CYP27)-O', 'was-O', 'identified-O', 'by-O', 'sequencing-O', 'amplified-O', 'CYP27-O', 'gene-O', 'products-O', 'from-O', 'a-O', 'patient-O', 'with-O', 'cerebrotendinous-B-SpecificDisease', 'xanthomatosis-I-SpecificDisease', '(CTX).-O', 'The-O', 'mutation-O', 'changed-O', 'the-O', 'adrenodoxin-O', 'cofactor-O', 'binding-O', 'residue-O', '362Arg-O', 'to-O', '362Ser-O', '(CGT-O', '362Arg-O', 'to-O', 'AGT-O', '362Ser),-O', 'and-O', 'was-O', 'responsible-O', 'for-O', 'deficiency-O', 'in-O', 'the-O', 'sterol-O', '27-hydroxylase-O', 'activity,-O', 'as-O', 'confirmed-O', 'by-O', 'expression-O', 'of-O', 'mutant-O', 'cDNA-O', 'into-O', 'COS-1-O', 'cells.-O']
['Quantitative-O', 'analysis-O', 'showed-O', 'that-O', 'the-O', 'expression-O', 'of-O', 'CYP27-B-Modifier', 'gene-O', 'mRNA-O', 'in-O', 'the-O', 'patient-O', 'represented-O', '52.-O']
['5%-O', 'of-O', 'the-O', 'normal-O', 'level.-O']
['As-O', 'the-O', 'mutation-O', 'occurred-O', 'at-O', 'the-O', 'penultimate-O', 'nucleotide-O', 'of-O', 'exon-O', '6-O', '(-2-O', 'position-O', 'of-O', 'exon-O', '6-intron-O', '6-O', 'splice-O', 'site)-O', 'of-O', 'the-O', 'gene,-O', 'we-O', 'hypothesized-O', 'that-O', 'the-O', 'mutation-O', 'may-O', 'partially-O', 'affect-O', 'the-O', 'normal-O', 'splicing-O', 'efficiency-O', 'in-O', 'exon-O', '6-O', 'and-O', 'cause-O', 'alternative-O', 'splicing-O', 'elsewhere,-O', 'which-O', 'resulted-O', 'in-O', 'decreased-O', 'transcript-O', 'in-O', 'the-O', 'patient.-O']
['Transfection-O', 'of-O', 'constructed-O', 'minigenes,-O', 'with-O', 'or-O', 'without-O', 'the-O', 'mutation,-O', 'into-O', 'COS-1-O', 'cells-O', 'confirmed-O', 'that-O', 'the-O', 'mutant-O', 'minigene-O', 'was-O', 'responsible-O', 'for-O', 'a-O', 'mRNA-O', 'species-O', 'alternatively-O', 'spliced-O', 'at-O', 'an-O', 'activated-O', 'cryptic-O', '5-O', 'splice-O', 'site-O', '88-O', 'bp-O', 'upstream-O', 'from-O', 'the-O', '3-O', 'end-O', 'of-O', 'exon-O', '6.-O']
['Our-O', 'data-O', 'suggest-O', 'that-O', 'the-O', 'C-O', 'to-O', 'A-O', 'mutation-O', 'at-O', 'the-O', 'penultimate-O', 'nucleotide-O', 'of-O', 'exon-O', '6-O', 'of-O', 'the-O', 'CYP27-O', 'gene-O', 'not-O', 'only-O', 'causes-O', 'the-O', 'deficiency-B-DiseaseClass', 'in-O', 'the-O', 'sterol-O', '27-hydroxylase-O', 'activity,-O', 'but-O', 'also-O', 'partially-O', 'leads-O', 'to-O', 'alternative-O', 'pre-mRNA-O', 'splicing-O', 'of-O', 'the-O', 'gene.-O']
['To-O', 'our-O', 'knowledge,-O', 'this-O', 'is-O', 'the-O', 'first-O', 'report-O', 'regarding-O', 'effects-O', 'on-O', 'pre-mRNA-O', 'splicing-O', 'of-O', 'a-O', 'mutation-O', 'at-O', 'the-O', '-2-O', 'position-O', 'of-O', 'a-O', '5-O', 'splice-O', 'site.-O']
['A-O', 'gene-O', 'encoding-O', 'a-O', 'transmembrane-O', 'protein-O', 'is-O', 'mutated-O', 'in-O', 'patients-O', 'with-O', 'diabetes-B-SpecificDisease', 'mellitus-I-SpecificDisease', 'and-O', 'optic-B-SpecificDisease', 'atrophy-I-SpecificDisease', '(Wolfram-B-SpecificDisease', 'syndrome).-I-SpecificDisease', 'Wolfram-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(WFS;-O', 'OMIM-O', '222300)-O', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'neurodegenerative-I-DiseaseClass', 'disorder-I-DiseaseClass', 'defined-O', 'by-O', 'young-onset-O', 'non-immune-O', 'insulin-dependent-B-SpecificDisease', 'diabetes-I-SpecificDisease', 'mellitus-I-SpecificDisease', 'and-O', 'progressive-O', 'optic-B-SpecificDisease', 'atrophy.-I-SpecificDisease', 'Linkage-O', 'to-O', 'markers-O', 'on-O', 'chromosome-O', '4p-O', 'was-O', 'confirmed-O', 'in-O', 'five-O', 'families.-O']
['On-O', 'the-O', 'basis-O', 'of-O', 'meiotic-O', 'recombinants-O', 'and-O', 'disease-associated-O', 'haplotypes,-O', 'the-O', 'WFS-B-Modifier', 'gene-O', 'was-O', 'localized-O', 'to-O', 'a-O', 'BAC/P1-O', 'contig-O', 'of-O', 'less-O', 'than-O', '250-O', 'kb.-O']
['Mutations-O', 'in-O', 'a-O', 'novel-O', 'gene-O', '(WFS1)-O', 'encoding-O', 'a-O', 'putative-O', 'transmembrane-O', 'protein-O', 'were-O', 'found-O', 'in-O', 'all-O', 'affected-O', 'individuals-O', 'in-O', 'six-O', 'WFS-B-Modifier', 'families,-O', 'and-O', 'these-O', 'mutations-O', 'were-O', 'associated-O', 'with-O', 'the-O', 'disease-O', 'phenotype.-O']
['WFS1-O', 'appears-O', 'to-O', 'function-O', 'in-O', 'survival-O', 'of-O', 'islet-O', 'beta-cells-O', 'and-O', 'neurons..-O']
['The-O', 'APC-B-Modifier', 'variants-O', 'I1307K-O', 'and-O', 'E1317Q-O', 'are-O', 'associated-O', 'with-O', 'colorectal-B-SpecificDisease', 'tumors,-I-SpecificDisease', 'but-O', 'not-O', 'always-O', 'with-O', 'a-O', 'family-O', 'history.-O']
['Classical-O', 'familial-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', '(FAP)-O', 'is-O', 'a-O', 'high-penetrance-O', 'autosomal-O', 'dominant-O', 'disease-O', 'that-O', 'predisposes-O', 'to-O', 'hundreds-O', 'or-O', 'thousands-O', 'of-O', 'colorectal-B-SpecificDisease', 'adenomas-I-SpecificDisease', 'and-O', 'carcinoma-I-SpecificDisease', 'and-O', 'that-O', 'results-O', 'from-O', 'truncating-O', 'mutations-O', 'in-O', 'the-O', 'APC-B-Modifier', 'gene.-O']
['A-O', 'variant-O', 'of-O', 'FAP-B-SpecificDisease', 'is-O', 'attenuated-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', 'coli,-I-SpecificDisease', 'which-O', 'results-O', 'from-O', 'germ-line-O', 'mutations-O', 'in-O', 'the-O', '5-O', 'and-O', '3-O', 'regions-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene.-O']
['Attenuated-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', 'coli-I-SpecificDisease', 'patients-O', 'have-O', '"-O', 'multiple-O', '"-O', 'colorectal-B-SpecificDisease', 'adenomas-I-SpecificDisease', '(typically-O', 'fewer-O', 'than-O', '100)-O', 'without-O', 'the-O', 'florid-O', 'phenotype-O', 'of-O', 'classical-O', 'FAP.-O', 'Another-O', 'group-O', 'of-O', 'patients-O', 'with-O', 'multiple-O', 'adenomas-O', 'has-O', 'no-O', 'mutations-O', 'in-O', 'the-O', 'APC-B-Modifier', 'gene,-O', 'and-O', 'their-O', 'phenotype-O', 'probably-O', 'results-O', 'from-O', 'variation-O', 'at-O', 'a-O', 'locus,-O', 'or-O', 'loci,-O', 'elsewhere-O', 'in-O', 'the-O', 'genome.-O']
['Recently,-O', 'however,-O', 'a-O', 'missense-O', 'variant-O', 'of-O', 'APC-O', '(I1307K)-O', 'was-O', 'described-O', 'that-O', 'confers-O', 'an-O', 'increased-O', 'risk-O', 'of-O', 'colorectal-B-SpecificDisease', 'tumors,-I-SpecificDisease', 'including-O', 'multiple-O', 'adenomas,-I-SpecificDisease', 'in-O', 'Ashkenazim.-O']
['We-O', 'have-O', 'studied-O', 'a-O', 'set-O', 'of-O', '164-O', 'patients-O', 'with-O', 'multiple-O', 'colorectal-B-DiseaseClass', 'adenomas-I-DiseaseClass', 'and/or-O', 'carcinoma-I-DiseaseClass', 'and-O', 'analyzed-O', 'codons-O', '1263-1377-O', '(exon-O', '15G)-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'for-O', 'germ-line-O', 'variants.-O']
['Three-O', 'patients-O', 'with-O', 'the-O', 'I1307K-B-Modifier', 'allele-O', 'were-O', 'detected,-O', 'each-O', 'of-O', 'Ashkenazi-O', 'descent.-O']
['Four-O', 'patients-O', 'had-O', 'a-O', 'germ-line-O', 'E1317Q-O', 'missense-O', 'variant-O', 'of-O', 'APC-B-Modifier', 'that-O', 'was-O', 'not-O', 'present-O', 'in-O', 'controls;-O', 'one-O', 'of-O', 'these-O', 'individuals-O', 'had-O', 'an-O', 'unusually-O', 'large-O', 'number-O', 'of-O', 'metaplastic-O', 'polyps-O', 'of-O', 'the-O', 'colorectum.-O', 'There-O', 'is-O', 'increasing-O', 'evidence-O', 'that-O', 'there-O', 'exist-O', 'germ-line-O', 'variants-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'that-O', 'predispose-O', 'to-O', 'the-O', 'development-O', 'of-O', 'multiple-O', 'colorectal-B-SpecificDisease', 'adenomas-I-SpecificDisease', 'and-O', 'carcinoma,-I-SpecificDisease', 'but-O', 'without-O', 'the-O', 'florid-O', 'phenotype-O', 'of-O', 'classical-O', 'FAP,-O', 'and-O', 'possibly-O', 'with-O', 'importance-O', 'for-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'risk-O', 'in-O', 'the-O', 'general-O', 'population..-O']
['Risk-O', 'reversals-O', 'in-O', 'predictive-O', 'testing-O', 'for-O', 'Huntington-B-SpecificDisease', 'disease-I-SpecificDisease.', 'The-O', 'first-O', 'predictive-O', 'testing-O', 'for-O', 'Huntington-B-SpecificDisease', 'disease-I-SpecificDisease', '(HD)-O', 'was-O', 'based-O', 'on-O', 'analysis-O', 'of-O', 'linked-O', 'polymorphic-O', 'DNA-O', 'markers-O', 'to-O', 'estimate-O', 'the-O', 'likelihood-O', 'of-O', 'inheriting-O', 'the-O', 'mutation-O', 'for-O', 'HD.-O', 'Limits-O', 'to-O', 'accuracy-O', 'included-O', 'recombination-O', 'between-O', 'the-O', 'DNA-O', 'markers-O', 'and-O', 'the-O', 'mutation,-O', 'pedigree-O', 'structure,-O', 'and-O', 'whether-O', 'DNA-O', 'samples-O', 'were-O', 'available-O', 'from-O', 'family-O', 'members.-O']
['With-O', 'direct-O', 'tests-O', 'for-O', 'the-O', 'HD-B-SpecificDisease', 'mutation,-O', 'we-O', 'have-O', 'assessed-O', 'the-O', 'accuracy-O', 'of-O', 'results-O', 'obtained-O', 'by-O', 'linkage-O', 'approaches-O', 'when-O', 'requested-O', 'to-O', 'do-O', 'so-O', 'by-O', 'the-O', 'test-O', 'individuals.-O']
['For-O', 'six-O', 'such-O', 'individuals,-O', 'there-O', 'was-O', 'significant-O', 'disparity-O', 'between-O', 'the-O', 'tests.-O']
['Three-O', 'went-O', 'from-O', 'a-O', 'decreased-O', 'risk-O', 'to-O', 'an-O', 'increased-O', 'risk,-O', 'while-O', 'in-O', 'another-O', 'three-O', 'the-O', 'risk-O', 'was-O', 'decreased.-O']
['Knowledge-O', 'of-O', 'the-O', 'potential-O', 'reasons-O', 'for-O', 'these-O', 'changes-O', 'in-O', 'results-O', 'and-O', 'impact-O', 'of-O', 'these-O', 'risk-O', 'reversals-O', 'on-O', 'both-O', 'patients-O', 'and-O', 'the-O', 'counseling-O', 'team-O', 'can-O', 'assist-O', 'in-O', 'the-O', 'development-O', 'of-O', 'strategies-O', 'for-O', 'the-O', 'prevention-O', 'and,-O', 'where-O', 'necessary,-O', 'management-O', 'of-O', 'a-O', 'risk-O', 'reversal-O', 'in-O', 'any-O', 'predictive-O', 'testing-O', 'program..-O']
['The-O', 'haptoglobin-gene-O', 'deletion-O', 'responsible-O', 'for-O', 'anhaptoglobinemia-O', 'We-O', 'have-O', 'found-O', 'an-O', 'allelic-O', 'deletion-O', 'of-O', 'the-O', 'haptoglobin-O', '(Hp)-O', 'gene-O', 'from-O', 'an-O', 'individual-O', 'with-O', 'anhaptoglobinemia-O', 'The-O', 'Hp-O', 'gene-O', 'cluster-O', 'consists-O', 'of-O', 'coding-O', 'regions-O', 'of-O', 'the-O', 'alpha-O', 'chain-O', 'and-O', 'beta-O', 'chain-O', 'of-O', 'the-O', 'haptoglobin-O', '(Hp)-O', 'gene-O', 'and-O', 'of-O', 'the-O', 'alpha-O', 'chain-O', 'and-O', 'beta-O', 'chain-O', 'of-O', 'the-O', 'haptoglobin-related-O', 'gene-O', '(Hpr),-O', 'in-O', 'tandem-O', 'from-O', 'the-O', '5-O', 'side.-O']
['Southern-O', 'blot-O', 'and-O', 'PCR-O', 'analyses-O', 'have-O', 'indicated-O', 'that-O', 'the-O', 'individual-O', 'with-O', 'anhaptoglobinemia-B-SpecificDisease', 'was-O', 'homozygous-O', 'for-O', 'the-O', 'gene-O', 'deletion-O', 'and-O', 'that-O', 'the-O', 'gene-O', 'deletion-O', 'was-O', 'included-O', 'at-O', 'least-O', 'from-O', 'the-O', 'promoter-O', 'region-O', 'of-O', 'Hp-O', 'to-O', 'Hpr-O', 'alpha-O', 'but-O', 'not-O', 'to-O', 'Hpr-O', 'beta-O', '(Hpdel)-O', 'In-O', 'addition,-O', 'we-O', 'found-O', 'seven-O', 'individuals-O', 'with-O', 'hypohaptoglobinemia-B-SpecificDisease', 'in-O', 'three-O', 'families,-O', 'and-O', 'the-O', 'genotypes-O', 'of-O', 'six-O', 'of-O', 'the-O', 'seven-O', 'individuals-O', 'were-O', 'found-O', 'to-O', 'be-O', 'Hp2/Hpdel-O']
['The-O', 'phenotypes-O', 'and-O', 'genotypes-O', 'in-O', 'one-O', 'of-O', 'these-O', 'three-O', 'families-O', 'showed-O', 'the-O', 'father-O', 'to-O', 'be-O', 'hypohaptoglobinemic-O', '(Hp2)-B-SpecificDisease', 'and-O', 'Hp2/Hpdel,-B-SpecificDisease', 'the-O', 'mother-O', 'to-O', 'be-O', 'Hp2-1-B-SpecificDisease', 'and-O', 'Hp1/Hp2,-B-SpecificDisease', 'one-O', 'of-O', 'the-O', 'two-O', 'children-O', 'to-O', 'be-O', 'hypohaptoglobinemic-O', '(Hp2)-B-SpecificDisease', 'and-O', 'Hp2/Hpdel,-B-SpecificDisease', 'and-O', 'the-O', 'other-O', 'child-O', 'to-O', 'be-O', 'Hp1-B-SpecificDisease', 'and-O', 'Hp1/Hpdel,-B-SpecificDisease', 'showing-O', 'an-O', 'anomalous-O', 'inheritance-O', 'of-O', 'Hp-O', 'phenotypes-O', 'in-O', 'the-O', 'child-O', 'with-O', 'Hp1.-O']
['The-O', 'Hp2/Hpdel-O', 'individuals-O', 'had-O', 'an-O', 'extremely-O', 'low-O', 'level-O', 'of-O', 'Hp-O', '(mean-O', '+/-SD-O', '=', '0.-O']
['049-O', '+/-0.-O']
['043-O', 'mg/ml;-O', 'n-O', '=O', '6)-O', 'compared-O', 'with-O', 'the-O', 'level-O', '(1.-O']
['64-O', '+/-1.-O']
['07-O', 'mg/ml)-O', 'obtained-O', 'from-O', '52-O', 'healthy-O', 'volunteers-O', 'having-O', 'phenotype-O', 'Hp2,-O', 'whereas-O', 'the-O', 'serum-O', 'Hp-O', 'level-O', 'of-O', 'an-O', 'individual-O', 'with-O', 'Hp1/Hpdel-B-Modifier', 'was-O', '0.-O']
['50-O', 'mg/ml,-O', 'which-O', 'was-O', 'approximately-O', 'half-O', 'the-O', 'level-O', 'of-O', 'Hp-O', 'in-O', 'control-O', 'sera-O', 'from-O', 'the-O', 'Hp1-B-Modifier', 'phenotype-O', '(1.-O']
['26-O', '+/-0.-O']
['33-O', 'mg/ml;-O', 'n-O', '=', '9)-O', 'showing-O', 'a-O', 'gene-dosage-O', 'effect.-O']
['The-O', 'other-O', 'allele-O', '(Hp2)-O', 'of-O', 'individuals-O', 'with-O', 'Hp2/Hpdel-O', 'was-O', 'found-O', 'to-O', 'have,-O', 'in-O', 'all-O', 'exons,-O', 'no-O', 'mutation,-O', 'by-O', 'DNA-O', 'sequencing.-O']
['On-O', 'the-O', 'basis-O', 'of-O', 'the-O', 'present-O', 'study,-O', 'the-O', 'mechanism-O', 'of-O', 'anhaptoglobinemia-B-DiseaseClass', 'and-O', 'the-O', 'mechanism-O', 'of-O', 'anomalous-O', 'inheritance-O', 'of-O', 'Hp-O', 'phenotypes-O', 'were-O', 'well-O', 'explained.-O']
['However,-O', 'the-O', 'mechanism-O', 'of-O', 'hypohaptoglobinemia-B-DiseaseClass', 'remains-O', 'unknown-O']
['Sperm-O', 'DNA-O', 'analysis-O', 'in-O', 'a-O', 'Friedreich-B-SpecificDisease', 'ataxia-I-SpecificDisease', 'premutation-O', 'carrier-O', 'suggests-O', 'both-O', 'meiotic-O', 'and-O', 'mitotic-O', 'expansion-O', 'in-O', 'the-O', 'FRDA-B-Modifier', 'gene.-O']
['Friedreich-B-SpecificDisease', 'ataxia-I-SpecificDisease', 'is-O', 'usually-O', 'caused-O', 'by-O', 'an-O', 'expansion-O', 'of-O', 'a-O', 'GAA-O', 'trinucleotide-O', 'repeat-O', 'in-O', 'intron-O', '1-O', 'of-O', 'the-O', 'FRDA-B-Modifier', 'gene.-O']
['Occasionally,-O', 'a-O', 'fully-O', 'expanded-O', 'allele-O', 'has-O', 'been-O', 'found-O', 'to-O', 'arise-O', 'from-O', 'a-O', 'premutation-O', 'of-O', '100-O', 'or-O', 'less-O', 'triplet-O', 'repeats.-O']
['We-O', 'have-O', 'examined-O', 'the-O', 'sperm-O', 'DNA-O', 'of-O', 'a-O', 'premutation-B-Modifier', 'carrier.-O']
['This-O', 'mans-O', 'leucocyte-O', 'DNA-O', 'showed-O', 'one-O', 'normal-O', 'allele-O', 'and-O', 'one-O', 'allele-O', 'of-O', 'approximately-O', '100-O', 'repeats.-O']
['His-O', 'sperm-O', 'showed-O', 'an-O', 'expanded-O', 'allele-O', 'in-O', 'a-O', 'tight-O', 'range-O', 'centering-O', 'on-O', 'a-O', 'size-O', 'of-O', 'approximately-O', '320-O', 'trinucleotide-O', 'repeats.-O']
['His-O', 'affected-O', 'son-O', 'has-O', 'repeat-O', 'sizes-O', 'of-O', '1040-O', 'and-O', '540.-O']
['These-O', 'data-O', 'suggest-O', 'that-O', 'expansion-O', 'occurs-O', 'in-O', 'two-O', 'stages,-O', 'the-O', 'first-O', 'during-O', 'meiosis-O', 'followed-O', 'by-O', 'a-O', 'second-O', 'mitotic-O', 'expansion.-O']
['We-O', 'also-O', 'show-O', 'that-O', 'in-O', 'all-O', 'informative-O', 'carrier-O', 'father-O', 'to-O', 'affected-O', 'child-O', 'transmissions,-O', 'with-O', 'the-O', 'notable-O', 'exception-O', 'of-O', 'the-O', 'premutation-O', 'carrier,-O', 'the-O', 'expansion-O', 'size-O', 'decreases..-O']
['Cloning-O', 'of-O', 'a-O', 'novel-O', 'member-O', 'of-O', 'the-O', 'low-density-O', 'lipoprotein-O', 'receptor-O', 'family.-O']
['A-O', 'gene-O', 'encoding-O', 'a-O', 'novel-O', 'transmembrane-O', 'protein-O', 'was-O', 'identified-O', 'by-O', 'DNA-O', 'sequence-O', 'analysis-O', 'within-O', 'the-O', 'insulin-dependent-B-SpecificDisease', 'diabetes-I-SpecificDisease', 'mellitus-I-SpecificDisease', '(IDDM)-O', 'locus-O', 'IDDM4-O', 'on-O', 'chromosome-O', '11q13.-O']
['Based-O', 'on-O', 'its-O', 'chromosomal-O', 'position,-O', 'this-O', 'gene-O', 'is-O', 'a-O', 'candidate-O', 'for-O', 'conferring-O', 'susceptibility-O', 'to-O', 'diabetes.-O', 'The-O', 'gene,-O', 'termed-O', 'low-density-O', 'lipoprotein-O', 'receptor-O', 'related-O', 'protein-O', '5-O', '(LRP5),-O', 'encodes-O', 'a-O', 'protein-O', 'of-O', '1615-O', 'amino-O', 'acids-O', 'that-O', 'contains-O', 'conserved-O', 'modules-O', 'which-O', 'are-O', 'characteristic-O', 'of-O', 'the-O', 'low-density-O', 'lipoprotein-O', '(LDL)-O', 'receptor-O', 'family.-O']
['These-O', 'modules-O', 'include-O', 'a-O', 'putative-O', 'signal-O', 'peptide-O', 'for-O', 'protein-O', 'export,-O', 'four-O', 'epidermal-O', 'growth-O', 'factor-O', '(EGF)-O', 'repeats-O', 'with-O', 'associated-O', 'spacer-O', 'domains,-O', 'three-O', 'LDL-receptor-O', '(LDLR)-O', 'repeats,-O', 'a-O', 'single-O', 'transmembrane-O', 'spanning-O', 'domain,-O', 'and-O', 'a-O', 'cytoplasmic-O', 'domain.-O']
['The-O', 'encoded-O', 'protein-O', 'has-O', 'a-O', 'unique-O', 'organization-O', 'of-O', 'EGF-O', 'and-O', 'LDLR-O', 'repeats;-O', 'therefore,-O', 'LRP5-O', 'likely-O', 'represents-O', 'a-O', 'new-O', 'category-O', 'of-O', 'the-O', 'LDLR-B-Modifier', 'family.-O']
['Both-O', 'human-O', 'and-O', 'mouse-O', 'LRP5-O', 'cDNAs-O', 'have-O', 'been-O', 'isolated-O', 'and-O', 'the-O', 'encoded-O', 'mature-O', 'proteins-O', 'are-O', '95%-O', 'identical,-O', 'indicating-O', 'a-O', 'high-O', 'degree-O', 'of-O', 'evolutionary-O', 'conservation..-O']
['Maternal-B-SpecificDisease', 'disomy-I-SpecificDisease', 'and-O', 'Prader-Willi-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'consistent-O', 'with-O', 'gamete-O', 'complementation-O', 'in-O', 'a-O', 'case-O', 'of-O', 'familial-O', 'translocation-O', '(3;15)-O', '(p25;q11.2).-O', 'Maternal-B-SpecificDisease', 'uniparental-B-SpecificDisease', 'disomy-I-SpecificDisease', '(UPD)-O', 'for-O', 'chromosome-O', '15-O', 'is-O', 'responsible-O', 'for-O', 'an-O', 'estimated-O', '30%-O', 'of-O', 'cases-O', 'of-O', 'Prader-Willi-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(PWS).-O', 'We-O', 'report-O', 'on-O', 'an-O', 'unusual-O', 'case-O', 'of-O', 'maternal-B-SpecificDisease', 'disomy-I-SpecificDisease', '15-O', 'in-O', 'PWS-O', 'that-O', 'is-O', 'most-O', 'consistent-O', 'with-O', 'adjacent-1-O', 'segregation-O', 'of-O', 'a-O', 'paternal-O', 't-O', '(3;-O', '15)-O', '(p25;-O', 'q11.-O']
['2)-O', 'with-O', 'simultaneous-O', 'maternal-O', 'meiotic-O', 'nondisjunction-O', 'for-O', 'chromosome-O', '15.-O']
['The-O', 'patient-O', '(J.-O']
['B.),-O', 'a-O', '17-year-old-O', 'white-O', 'male,-O', 'with-O', 'PWS-B-SpecificDisease', ',-O', 'was-O', 'found-O', 'to-O', 'have-O', '47-O', 'chromosomes-O', 'with-O', 'a-O', 'supernumerary,-O', 'paternal-O', 'der-O', '(15)-O', 'consisting-O', 'of-O', 'the-O', 'short-O', 'arm-O', 'and-O', 'the-O', 'proximal-O', 'long-O', 'arm-O', 'of-O', 'chromosome-O', '15,-O', 'and-O', 'distal-O', 'chromosome-O', 'arm-O', '3p.-O']
['The-O', 't-O', '(3;-O', '15)-O', 'was-O', 'present-O', 'in-O', 'the-O', 'balanced-O', 'state-O', 'in-O', 'the-O', 'patients-O', 'father-O', 'and-O', 'a-O', 'sister.-O']
['Fluorescent-O', 'in-O', 'situ-O', 'hybridization-O', 'analysis-O', 'demonstrated-O', 'that-O', 'the-O', 'PWS-B-SpecificDisease', 'critical-O', 'region-O', 'resided-O', 'on-O', 'the-O', 'derivative-O', 'chromosome-O', '3-O', 'and-O', 'that-O', 'there-O', 'was-O', 'no-O', 'deletion-O', 'of-O', 'the-O', 'PWS-B-SpecificDisease', 'region-O', 'on-O', 'the-O', 'normal-O', 'pair-O', 'of-O', '15s-O', 'present-O', 'in-O', 'J.-O']
['B.-O']
['Methylation-O', 'analysis-O', 'at-O', 'exon-O', 'alpha-O', 'of-O', 'the-O', 'small-O', 'nuclear-O', 'ribonucleoprotein-associated-O', 'polypeptide-O', 'N-O', '(SNRPN)-O', 'gene-O', 'showed-O', 'a-O', 'pattern-O', 'characteristic-O', 'of-O', 'only-O', 'the-O', 'maternal-O', 'chromosome-O', '15-O', 'in-O', 'J.-O']
['B.-O']
['Maternal-B-SpecificDisease', 'disomy-I-SpecificDisease', 'was-O', 'confirmed-O', 'by-O', 'polymerase-O', 'chain-O', 'reaction-O', 'analysis-O', 'of-O', 'microsatellite-O', 'repeats-O', 'at-O', 'the-O', 'gamma-aminobutyric-O', 'acid-O', 'receptor-O', 'beta3-O', 'subunit-O', '(GABRB3)-O', 'locus.-O']
['A-O', 'niece-O', '(B.-O']
['B.)-O', 'with-O', '45-O', 'chromosomes-O', 'and-O', 'the-O', 'derivative-O', '3-O', 'but-O', 'without-O', 'the-O', 'der-O', '(15)-O', 'demonstrated-O', 'a-O', 'phenotype-O', 'consistent-O', 'with-O', 'that-O', 'reported-O', 'for-O', 'haploinsufficiency-B-CompositeMention', 'of-O', 'distal-O', '3-O', 'p.-O']
['Uniparental-B-SpecificDisease', 'disomy-I-SpecificDisease', 'associated-O', 'with-O', 'unbalanced-O', 'segregation-O', 'of-O', 'non-Robertsonian-O', 'translocations-O', 'has-O', 'been-O', 'reported-O', 'previously-O', 'but-O', 'has-O', 'not,-O', 'to-O', 'our-O', 'knowledge,-O', 'been-O', 'observed-O', 'in-O', 'a-O', 'case-O', 'of-O', 'PWS.-B-SpecificDisease', 'Furthermore,-O', 'our-O', 'findings-O', 'are-O', 'best-O', 'interpreted-O', 'as-O', 'true-O', 'gamete-O', 'complementation-O', 'resulting-O', 'in-O', 'maternal-O', 'UPD-B-SpecificDisease', '15-O', 'and-O', 'PWS.-B-SpecificDisease']
['Reversal-O', 'of-O', 'severe-O', 'hypertrophic-O', 'cardiomyopathy-B-SpecificDisease', 'and-O', 'excellent-O', 'neuropsychologic-O', 'outcome-O', 'in-O', 'very-long-chain-O', 'acyl-coenzyme-O', 'A-O', 'dehydrogenase-O', 'deficiency.-I-SpecificDisease', 'Very-long-chain-O', 'acyl-coenzyme-O', 'A-O', 'dehydrogenase-O', '(VLCAD)-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'is-O', 'a-O', 'disorder-O', 'of-O', 'fatty-O', 'acid-O', 'beta-O', 'oxidation-O', 'that-O', 'reportedly-O', 'has-O', 'high-O', 'rates-O', 'of-O', 'morbidity-O', 'and-O', 'mortality.-O']
['We-O', 'describe-O', 'the-O', 'outcome-O', 'of-O', 'a-O', '5-year-old-O', 'girl-O', 'with-O', 'VLCAD-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'who-O', 'was-O', 'first-O', 'seen-O', 'at-O', '5-O', 'months-O', 'of-O', 'age-O', 'with-O', 'severe-O', 'hypertrophic-B-SpecificDisease', 'cardiomyopathy,-I-SpecificDisease', 'hepatomegaly,-O', 'encephalopathy,-O', 'and-O', 'hypotonia.-O', 'Biochemical-O', 'studies-O', 'indicated-O', 'VLCAD-O', 'deficiency-O', 'caused-O', 'by-O', 'a-O', 'stable-O', 'yet-O', 'inactive-O', 'enzyme.-O']
['Molecular-O', 'genetic-O', 'analysis-O', 'of-O', 'her-O', 'VLCAD-O', 'gene-O', 'revealed-O', 'a-O', 'T1372C-O', '(F458L)-O', 'missense-O', 'mutation-O', 'and-O', 'a-O', '1668-O', 'ACAG-O', '1669-O', 'splice-O', 'site-O', 'mutation.-O']
['After-O', 'initial-O', 'treatment-O', 'with-O', 'intravenous-O', 'glucose-O', 'and-O', 'carnitine,-O', 'the-O', 'patient-O', 'has-O', 'thrived-O', 'on-O', 'a-O', 'low-fat-O', 'diet-O', 'supplemented-O', 'with-O', 'medium-chain-O', 'triglyceride-O', 'oil-O', 'and-O', 'carnitine-O', 'and-O', 'avoidance-O', 'of-O', 'fasting.-O']
['Her-O', 'ventricular-B-SpecificDisease', 'hypertrophy-I-SpecificDisease', 'resolved-O', 'significantly-O', 'over-O', '1-O', 'year,-O', 'and-O', 'cognitively,-O', 'she-O', 'is-O', 'in-O', 'the-O', 'superior-O', 'range-O', 'for-O', 'age.-O']
['Clinical-O', 'recognition-O', 'of-O', 'VLCAD-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'is-O', 'important-O', 'because-O', 'it-O', 'is-O', 'one-O', 'of-O', 'the-O', 'few-O', 'directly-O', 'treatable-O', 'causes-O', 'of-O', 'cardiomyopathy-B-DiseaseClass', 'in-O', 'children..-O']
['Two-O', 'frequent-O', 'missense-O', 'mutations-O', 'in-O', 'Pendred-B-Modifier', 'syndrome.-I-Modifier', 'Pendred-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'disorder-I-DiseaseClass', 'characterized-O', 'by-O', 'early-O', 'childhood-O', 'deafness-I-SpecificDisease', 'and-O', 'goiter.-I-SpecificDisease', 'A-O', 'century-O', 'after-O', 'its-O', 'recognition-O', 'as-O', 'a-O', 'syndrome-O', 'by-O', 'Vaughan-O', 'Pendred,-O', 'the-O', 'disease-O', 'gene-O', '(PDS)-O', 'was-O', 'mapped-O', 'to-O', 'chromosome-O', '7q22-q31.-O']
['1-O', 'and,-O', 'recently,-O', 'found-O', 'to-O', 'encode-O', 'a-O', 'putative-O', 'sulfate-O', 'transporter.-O']
['We-O', 'performed-O', 'mutation-O', 'analysis-O', 'of-O', 'the-O', 'PDS-B-Modifier', 'gene-O', 'in-O', 'patients-O', 'from-O', '14-O', 'Pendred-B-SpecificDisease', 'families-O', 'originating-O', 'from-O', 'seven-O', 'countries-O', 'and-O', 'identified-O', 'all-O', 'mutations.-O']
['The-O', 'mutations-O', 'include-O', 'three-O', 'single-O', 'base-O', 'deletions,-O', 'one-O', 'splice-O', 'site-O', 'mutation-O', 'and-O', '10-O', 'missense-O', 'mutations.-O']
['One-O', 'missense-O', 'mutation-O', '(L236P)-O', 'was-O', 'found-O', 'in-O', 'a-O', 'homozygous-O', 'state-O', 'in-O', 'two-O', 'consanguineous-O', 'families-O', 'and-O', 'in-O', 'a-O', 'heterozygous-O', 'state-O', 'in-O', 'five-O', 'additional-O', 'non-consanguineous-O', 'families.-O']
['Another-O', 'missense-O', 'mutation-O', '(T416P)-O', 'was-O', 'found-O', 'in-O', 'a-O', 'homozygous-O', 'state-O', 'in-O', 'one-O', 'family-O', 'and-O', 'in-O', 'a-O', 'heterozygous-O', 'state-O', 'in-O', 'four-O', 'families.-O']
['Pendred-B-SpecificDisease', 'patients-O', 'in-O', 'three-O', 'non-consanguineous-O', 'families-O', 'were-O', 'shown-O', 'to-O', 'be-O', 'compound-O', 'heterozygotes-O', 'for-O', 'L236P-O', 'and-O', 'T416P.-O']
['In-O', 'total,-O', 'one-O', 'or-O', 'both-O', 'of-O', 'these-O', 'mutations-O', 'were-O', 'found-O', 'in-O', 'nine-O', 'of-O', 'the-O', '14-O', 'families-O', 'analyzed.-O']
['The-O', 'identification-O', 'of-O', 'two-O', 'frequent-O', 'PDS-B-Modifier', 'mutations-O', 'will-O', 'facilitate-O', 'the-O', 'molecular-O', 'diagnosis-O', 'of-O', 'Pendred-B-SpecificDisease', 'syndrome.-I-SpecificDisease']
['Wilms-B-Modifier', 'tumor-I-Modifier', '1-O', 'and-O', 'Dax-1-O', 'modulate-O', 'the-O', 'orphan-O', 'nuclear-O', 'receptor-O', 'SF-1-O', 'in-O', 'sex-specific-O', 'gene-O', 'expression.-O']
['Products-O', 'of-O', 'steroidogenic-O', 'factor-O', '1-O', '(SF-1)-O', 'and-O', 'Wilms-B-Modifier', 'tumor-I-Modifier', '1-O', '(WT1)-O', 'genes-O', 'are-O', 'essential-O', 'for-O', 'mammalian-O', 'gonadogenesis-O', 'prior-O', 'to-O', 'sexual-O', 'differentiation.-O']
['In-O', 'males,-O', 'SF-1-O', 'participates-O', 'in-O', 'sexual-O', 'development-O', 'by-O', 'regulating-O', 'expression-O', 'of-O', 'the-O', 'polypeptide-O', 'hormone-O', 'Mullerian-O', 'inhibiting-O', 'substance-O', '(MIS).-O', 'Here,-O', 'we-O', 'show-O', 'that-O', 'WT1-B-Modifier', '-KTS-O', 'isoforms-O', 'associate-O', 'and-O', 'synergize-O', 'with-O', 'SF-1-O', 'to-O', 'promote-O', 'MIS-O', 'expression.-O']
['In-O', 'contrast,-O', 'WT1-O', 'missense-O', 'mutations,-O', 'associated-O', 'with-O', 'male-O', 'pseudohermaphroditism-B-DiseaseClass', 'in-O', 'Denys-Drash-B-SpecificDisease', 'syndrome,-I-SpecificDisease', 'fail-O', 'to-O', 'synergize-O', 'with-O', 'SF-1.-O']
['Additionally,-O', 'the-O', 'X-linked,-B-SpecificDisease', 'candidate-O', 'dosage-sensitive-O', 'sex-reversal-O', 'gene,-O', 'Dax-1,-O', 'antagonizes-O', 'synergy-O', 'between-O', 'SF-1-O', 'and-O', 'WT1,-O', 'most-O', 'likely-O', 'through-O', 'a-O', 'direct-O', 'interaction-O', 'with-O', 'SF-1.-O']
['We-O', 'propose-O', 'that-O', 'WT1-O', 'and-O', 'Dax-1-O', 'functionally-O', 'oppose-O', 'each-O', 'other-O', 'in-O', 'testis-O', 'development-O', 'by-O', 'modulating-O', 'SF-1-mediated-O', 'transactivation..-O']
['Are-O', 'Dp71-O', 'and-O', 'Dp140-O', 'brain-O', 'dystrophin-O', 'isoforms-O', 'related-O', 'to-O', 'cognitive-O', 'impairment-O', 'in-O', 'Duchenne-B-SpecificDisease', 'muscular-I-SpecificDisease', 'dystrophy?-I-SpecificDisease', 'Molecular-O', 'study-O', 'and-O', 'neuropsychological-O', 'analysis-O', 'were-O', 'performed-O', 'concurrently-O', 'on-O', '49-O', 'patients-O', 'with-O', 'Duchenne-B-SpecificDisease', 'muscular-I-SpecificDisease', 'dystrophy-O', '(DMD)-O', 'in-O', 'order-O', 'to-O', 'find-O', 'a-O', 'molecular-O', 'explanation-O', 'for-O', 'the-O', 'cognitive-O', 'impairment-O', 'observed-O', 'in-O', 'most-O', 'DMD-O', 'patients.-O']
['Complete-O', 'analysis-O', 'of-O', 'the-O', 'dystrophin-O', 'gene-O', 'was-O', 'performed-O', 'to-O', 'define-O', 'the-O', 'localization-O', 'of-O', 'deletions-O', 'and-O', 'duplications-O', 'in-O', 'relation-O', 'to-O', 'the-O', 'different-O', 'DMD-B-Modifier', 'promoters.-O']
['Qualitative-O', 'analysis-O', 'of-O', 'the-O', 'Dp71-O', 'transcript-O', 'and-O', 'testing-O', 'for-O', 'the-O', 'specific-O', 'first-O', 'exon-O', 'of-O', 'Dp140-O', 'were-O', 'also-O', 'carried-O', 'out.-O']
['Neuropsychological-O', 'analysis-O', 'assessed-O', 'verbal-O', 'and-O', 'visuospatial-O', 'intelligence,-O', 'verbal-O', 'memory,-O', 'and-O', 'reading-O', 'skills.-O']
['Comparison-O', 'of-O', 'molecular-O', 'and-O', 'psychometric-O', 'findings-O', 'demonstrated-O', 'that-O', 'deletions-O', 'and-O', 'duplications-O', 'that-O', 'were-O', 'localized-O', 'in-O', 'the-O', 'distal-O', 'part-O', 'of-O', 'the-O', 'gene-O', 'seemed-O', 'to-O', 'be-O', 'preferentially-O', 'associated-O', 'with-O', 'cognitive-O', 'impairment.-O', 'Two-O', 'altered-O', 'Dp71-O', 'transcripts-O', 'and-O', 'two-O', 'deleted-O', 'Dp140-O', 'DNA-O', 'sequences-O', 'were-O', 'found-O', 'in-O', 'four-O', 'patients-O', 'with-O', 'severe-O', 'cerebral-O', 'dysfunction.-O', 'These-O', 'findings-O', 'suggest-O', 'that-O', 'some-O', 'sequences-O', 'located-O', 'in-O', 'the-O', 'distal-O', 'part-O', 'of-O', 'the-O', 'gene-O', 'and,-O', 'in-O', 'particular,-O', 'some-O', 'DMD-B-Modifier', 'isoforms-O', 'expressed-O', 'in-O', 'the-O', 'brain-B-DiseaseClass', 'may-O', 'be-O', 'related-O', 'to-O', 'the-O', 'cognitive-O', 'impairment-O', 'associated-O', 'with-O', 'DMD..-O']
['Genomic-O', 'organization-O', 'of-O', 'the-O', 'UBE3A/E6-AP-B-Modifier', 'gene-O', 'and-O', 'related-O', 'pseudogenes.-O']
['The-O', 'UBE3A-B-Modifier', 'gene-O', 'encodes-O', 'the-O', 'E6-AP-O', 'ubiquitin-protein-O', 'ligase-O', 'and-O', 'has-O', 'recently-O', 'been-O', 'shown-O', 'to-O', 'be-O', 'mutated-O', 'in-O', 'Angelman-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'patients-O', 'who-O', 'lack-O', '15q11-q13-O', 'deletions-O', 'or-O', 'chromosome-O', '15-O', 'paternal-B-SpecificDisease', 'uniparental-I-SpecificDisease', 'disomy.-O', 'Previous-O', 'UBE3A-O', 'cDNA-O', 'analysis-O', 'has-O', 'shown-O', 'a-O', 'coding-O', 'region-O', 'of-O', 'approximately-O', '2.-O']
['6-O', 'kb-O', 'and-O', 'a-O', '3-untranslated-O', 'region-O', '(UTR)-O', 'of-O', '<-O', '50-O', 'bp,-O', 'whereas-O', 'Northern-O', 'analysis-O', 'has-O', 'indicated-O', 'mRNA-O', 'sizes-O', 'of-O', '5-8-O', 'kb.-O']
['We-O', 'have-O', 'analyzed-O', 'additional-O', 'cDNA-O', 'clones-O', 'and-O', 'provide-O', 'evidence-O', 'for-O', 'an-O', 'additional-O', '0.-O']
['5-O', 'kb-O', 'of-O', '5-UTR-O', 'and-O', '>-O', '2-O', 'kb-O', 'of-O', '3-UTR-O']
['We-O', 'have-O', 'established-O', 'the-O', 'genomic-O', 'organization-O', 'of-O', 'UBE3A-O', 'and-O', 'the-O', 'sequence-O', 'of-O', 'intron-exon-O', 'borders.-O']
['We-O', 'have-O', 'also-O', 'mapped-O', 'two-O', 'highly-O', 'homologous-O', 'processed-O', 'pseudogenes,-O', 'UBE3AP1-O', 'and-O', 'UBE3AP2,-O', 'to-O', 'chromosomes-O', '2-O', 'and-O', '21,-O', 'respectively,-O', 'and-O', 'determined-O', 'their-O', 'genomic-O', 'organization.-O']
['These-O', 'results-O', 'will-O', 'form-O', 'the-O', 'basis-O', 'for-O', 'studies-O', 'of-O', 'mutation-O', 'and-O', 'imprinting-O', 'of-O', 'UBE3A-O']
['Aspartylglucosaminuria-B-SpecificDisease', 'among-O', 'Palestinian-O', 'Arabs.-O']
['Aspartylglucosaminuria-B-SpecificDisease', '(AGU)-O', 'is-O', 'a-O', 'rare-O', 'disorder-I-DiseaseClass', 'of-O', 'glycoprotein-O', 'metabolism-O', 'caused-O', 'by-O', 'the-O', 'deficiency-B-SpecificDisease', 'of-O', 'the-O', 'lysosomal-O', 'enzyme-O', 'aspartylglucosaminidase-I-SpecificDisease', '(AGA).-O', 'AGU-O', 'is-O', 'inherited-O', 'as-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'trait-O', 'and-O', 'occurs-O', 'with-O', 'a-O', 'high-O', 'frequency-O', 'in-O', 'Finland-O', 'because-O', 'of-O', 'a-O', 'founder-O', 'effect.-O']
['While-O', 'very-O', 'few-O', 'patients-O', 'with-O', 'AGU-B-Modifier', 'have-O', 'been-O', 'reported-O', 'from-O', 'non-Finnish-O', 'origin,-O', 'we-O', 'diagnosed-O', 'the-O', 'disorder-O', 'in-O', '8-O', 'patients-O', 'originating-O', 'from-O', '3-O', 'unrelated-O', 'families,-O', 'all-O', 'Palestinian-O', 'Arabs-O', 'from-O', 'the-O', 'region-O', 'of-O', 'Jerusalem.-O']
['The-O', 'clinical-O', 'diagnosis-O', 'of-O', 'AGU-B-SpecificDisease', 'is-O', 'often-O', 'difficult,-O', 'in-O', 'particular-O', 'early-O', 'in-O', 'the-O', 'course-O', 'of-O', 'the-O', 'disease,-O', 'and-O', 'most-O', 'of-O', 'the-O', 'patients-O', 'are-O', 'diagnosed-O', 'after-O', 'the-O', 'age-O', 'of-O', '5-O', 'years.-O']
['However,-O', 'since-O', 'these-O', 'patients-O', 'excrete-O', 'early-O', 'large-O', 'amounts-O', 'of-O', 'aspartylglucosamine-O', 'in-O', 'urine,-O', 'biochemical-O', 'screening-O', 'is-O', 'easy-O', 'by-O', 'urine-O', 'chromatography..-O']
['Segregation-O', 'distortion-O', 'in-O', 'myotonic-B-SpecificDisease', 'dystrophy.-I-SpecificDisease', 'Myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM)-O', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'disease-O', 'which,-O', 'in-O', 'the-O', 'typical-O', 'pedigree,-O', 'shows-O', 'a-O', 'three-O', 'generation-O', 'anticipation-O', 'cascade.-O']
['This-O', 'results-O', 'in-O', 'infertility-O', 'and-O', 'congenital-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(CDM)-O', 'with-O', 'the-O', 'disappearance-O', 'of-O', 'DM-B-Modifier', 'in-O', 'that-O', 'pedigree.-O']
['The-O', 'concept-O', 'of-O', 'segregation-O', 'distortion,-O', 'where-O', 'there-O', 'is-O', 'preferential-O', 'transmission-O', 'of-O', 'the-O', 'larger-O', 'allele-O', 'at-O', 'the-O', 'DM-B-Modifier', 'locus,-O', 'has-O', 'been-O', 'put-O', 'forward-O', 'to-O', 'explain-O', 'partially-O', 'the-O', 'maintenance-O', 'of-O', 'DM-B-SpecificDisease', 'in-O', 'the-O', 'population.-O']
['In-O', 'a-O', 'survey-O', 'of-O', 'DM-B-Modifier', 'in-O', 'Northern-O', 'Ireland,-O', '59-O', 'pedigrees-O', 'were-O', 'ascertained.-O']
['Sibships-O', 'where-O', 'the-O', 'status-O', 'of-O', 'all-O', 'the-O', 'members-O', 'had-O', 'been-O', 'identified-O', 'were-O', 'examined-O', 'to-O', 'determine-O', 'the-O', 'transmission-O', 'of-O', 'the-O', 'DM-B-Modifier', 'expansion-O', 'from-O', 'affected-O', 'parents-O', 'to-O', 'their-O', 'offspring.-O']
['Where-O', 'the-O', 'transmitting-O', 'parent-O', 'was-O', 'male,-O', '58.-O']
['3%-O', 'of-O', 'the-O', 'offspring-O', 'were-O', 'affected,-O', 'and-O', 'in-O', 'the-O', 'case-O', 'of-O', 'a-O', 'female-O', 'transmitting-O', 'parent,-O', '68.-O']
['7%-O', 'were-O', 'affected-O']
['Studies-O', 'on-O', 'meiotic-O', 'drive-O', 'in-O', 'DM-B-Modifier', 'have-O', 'shown-O', 'increased-O', 'transmission-O', 'of-O', 'the-O', 'larger-O', 'allele-O', 'at-O', 'the-O', 'DM-B-Modifier', 'locus-O', 'in-O', 'non-DM-O', 'heterozygotes-O', 'for-O', 'CTGn.-O']
['This-O', 'study-O', 'provides-O', 'further-O', 'evidence-O', 'that-O', 'the-O', 'DM-B-Modifier', 'expansion-O', 'tends-O', 'to-O', 'be-O', 'transmitted-O', 'preferentially.-O']
['A-O', 'genome-wide-O', 'search-O', 'for-O', 'chromosomal-O', 'loci-O', 'linked-O', 'to-O', 'mental-B-DiseaseClass', 'health-O', 'wellness-O', 'in-O', 'relatives-O', 'at-O', 'high-O', 'risk-O', 'for-O', 'bipolar-B-SpecificDisease', 'affective-I-SpecificDisease', 'disorder-I-SpecificDisease', 'among-O', 'the-O', 'Old-O', 'Order-O', 'Amish.-O']
['Bipolar-B-SpecificDisease', 'affective-I-SpecificDisease', 'disorder-I-SpecificDisease', '(BPAD;-O', 'manic-depressive-I-SpecificDisease', 'illness)-I-SpecificDisease', 'is-O', 'characterized-O', 'by-O', 'episodes-O', 'of-O', 'mania-O', 'and/or-O', 'hypomania-O', 'interspersed-O', 'with-O', 'periods-O', 'of-O', 'depression-O', '.', 'Compelling-O', 'evidence-O', 'supports-O', 'a-O', 'significant-O', 'genetic-O', 'component-O', 'in-O', 'the-O', 'susceptibility-O', 'to-O', 'develop-O', 'BPAD-O', '.', 'To-O', 'date,-O', 'however,-O', 'linkage-O', 'studies-O', 'have-O', 'attempted-O', 'only-O', 'to-O', 'identify-O', 'chromosomal-O', 'loci-O', 'that-O', 'cause-O', 'or-O', 'increase-O', 'the-O', 'risk-O', 'of-O', 'developing-O', 'BPAD-O', '.', 'To-O', 'determine-O', 'whether-O', 'there-O', 'could-O', 'be-O', 'protective-O', 'alleles-O', 'that-O', 'prevent-O', 'or-O', 'reduce-O', 'the-O', 'risk-O', 'of-O', 'developing-O', 'BPAD,-O', 'similar-O', 'to-O', 'what-O', 'is-O', 'observed-O', 'in-O', 'other-O', 'genetic-O', 'disorders,-O', 'we-O', 'used-O', 'mental-O', 'health-O', 'wellness-O', '(absence-O', 'of-O', 'any-O', 'psychiatric-O', 'disorder)-O', 'as-O', 'the-O', 'phenotype-O', 'in-O', 'our-O', 'genome-wide-O', 'linkage-O', 'scan-O', 'of-O', 'several-O', 'large-O', 'multigeneration-O', 'Old-O', 'Order-O', 'Amish-O', 'pedigrees-O', 'exhibiting-O', 'an-O', 'extremely-O', 'high-O', 'incidence-O', 'of-O', 'BPAD-O', '.', 'We-O', 'have-O', 'found-O', 'strong-O', 'evidence-O', 'for-O', 'a-O', 'locus-O', 'on-O', 'chromosome-O', '4p-O', 'at-O', 'D4S2949-O', '(maximum-O', 'GENEHUNTER-PLUS-O', 'nonparametric-O', 'linkage-O', 'score-O', '=', '4.-O']
['05,-O', 'P-O', '=O', '5.-O']
['22-O', 'x-O', '10-O', '(-4);-O', 'SIBPAL-O', 'Pempirical-O', 'value-O', '<-O', '3-O', 'x-O', '10-O', '(-5))-O', 'and-O', 'suggestive-O', 'evidence-O', 'for-O', 'a-O', 'locus-O', 'on-O', 'chromosome-O', '4q-O', 'at-O', 'D4S397-O', '(maximum-O', 'GENEHUNTER-PLUS-O', 'nonparametric-O', 'linkage-O', 'score-O', '=', '3.-O']
['29,-O', 'P-O', '=O', '2.-O']
['57-O', 'x-O', '10-O', '(-3);-O', 'SIBPAL-O', 'Pempirical-O', 'value-O', '<-O', '1-O', 'x-O', '10-O', '(-3))-O', 'that-O', 'are-O', 'linked-O', 'to-O', 'mental-B-DiseaseClass', 'health-O', 'wellness.-O']
['These-O', 'findings-O', 'are-O', 'consistent-O', 'with-O', 'the-O', 'hypothesis-O', 'that-O', 'certain-O', 'alleles-O', 'could-O', 'prevent-O', 'or-O', 'modify-O', 'the-O', 'clinical-O', 'manifestations-O', 'of-O', 'BPAD-B-SpecificDisease', 'and-O', 'perhaps-O', 'other-O', 'related-O', 'affective-I-SpecificDisease', 'disorders.-I-SpecificDisease']
['Identification-O', 'of-O', 'constitutional-O', 'WT1-O', 'mutations,-O', 'in-O', 'patients-O', 'with-O', 'isolated-B-SpecificDisease', 'diffuse-I-SpecificDisease', 'mesangial-I-SpecificDisease', 'sclerosis,-I-SpecificDisease', 'and-O', 'analysis-O', 'of-O', 'genotype/phenotype-O', 'correlations-O', 'by-O', 'use-O', 'of-O', 'a-O', 'computerized-O', 'mutation-O', 'database.-O']
['Constitutional-O', 'mutations-O', 'of-O', 'the-O', 'WT1-O', 'gene,-O', 'encoding-O', 'a-O', 'zinc-finger-O', 'transcription-O', 'factor-O', 'involved-O', 'in-O', 'renal-O', 'and-O', 'gonadal-O', 'development,-O', 'are-O', 'found-O', 'in-O', 'most-O', 'patients-O', 'with-O', 'Denys-Drash-B-SpecificDisease', 'syndrome,-I-SpecificDisease', '(DDS),-O', 'or-O', 'diffuse-O', 'mesangial-B-SpecificDisease', 'sclerosis,-I-SpecificDisease', '(DMS)-O', 'associated-O', 'with-O', 'pseudohermaphroditism,-B-DiseaseClass', 'and/or-O', 'Wilms-B-SpecificDisease', 'tumor,-I-SpecificDisease', '(WT).-O', 'Most-O', 'mutations-O', 'in-O', 'DDS-O', 'patients-O', 'lie-O', 'in-O', 'exon-O', '8-O', 'or-O', 'exon-O', '9,-O', 'encoding-O', 'zinc-O', 'finger-O', '2-O', 'or-O', 'zinc-O', 'finger-O', '3,-O', 'respectively,-O', 'with-O', 'a-O', 'hot-O', 'spot,-O', '(R394W)-O', 'in-O', 'exon-O', '9.-O']
['We-O', 'analyzed-O', 'a-O', 'series-O', 'of-O', '24-O', 'patients,-O', '10-O', 'with-O', 'isolated-O', 'DMS-O', '(IDMS),-O', '10-O', 'with-O', 'DDS,-O', 'and-O', '4-O', 'with-O', 'urogenital-B-DiseaseClass', 'abnormalities-I-DiseaseClass', 'and/or-O', 'WT.-O', 'We-O', 'report-O', 'WT1-O', 'heterozygous-O', 'mutations-O', 'in-O', '16-O', 'patients,-O', '4-O', 'of-O', 'whom-O', 'presented-O', 'with-O', 'IDMS.-O', 'One-O', 'male-O', 'and-O', 'two-O', 'female-O', 'IDMS-O', 'patients-O', 'with-O', 'WT1-O', 'mutations-O', 'underwent-O', 'normal-O', 'puberty.-O']
['Two-O', 'mutations-O', 'associated-O', 'with-O', 'IDMS-B-SpecificDisease', 'are-O', 'different-O', 'from-O', 'those-O', 'described-O', 'in-O', 'DDS-B-SpecificDisease', 'patients.-O']
['No-O', 'WT1-O', 'mutations-O', 'were-O', 'detected-O', 'in-O', 'the-O', 'six-O', 'other-O', 'IDMS-B-Modifier', 'patients,-O', 'suggesting-O', 'genetic-O', 'heterogeneity-O', 'of-O', 'this-O', 'disease.-O']
['We-O', 'analyzed-O', 'genotype/phenotype-O', 'correlations,-O', 'on-O', 'the-O', 'basis-O', 'of-O', 'the-O', 'constitution-O', 'of-O', 'a-O', 'WT1-O', 'mutation-O', 'database-O', 'of-O', '84-O', 'germ-line-O', 'mutations,-O', 'to-O', 'compare-O', 'the-O', 'distribution-O', 'and-O', 'type-O', 'of-O', 'mutations,-O', 'according-O', 'to-O', 'the-O', 'different-O', 'symptoms.-O']
['This-O', 'demonstrated-O', '(1)-O', 'the-O', 'association-O', 'between-O', 'mutations-O', 'in-O', 'exons-O', '8-O', 'and-O', '9-O', 'and-O', 'DMS;-O', '(2)-O', 'among-O', 'patients-O', 'with-O', 'DMS,-O', 'a-O', 'higher-O', 'frequency-O', 'of-O', 'exon-O', '8-O', 'mutations-O', 'among-O', '46,-O', 'XY-O', 'patients-O', 'with-O', 'female-O', 'phenotype-O', 'than-O', 'among-O', '46,-O', 'XY-O', 'patients-O', 'with-O', 'sexual-O', 'ambiguity-O', 'or-O', 'male-O', 'phenotype;-O', 'and-O', '(3)-O', 'statistically-O', 'significant-O', 'evidence-O', 'that-O', 'mutations-O', 'in-O', 'exons-O', '8-O', 'and-O', '9-O', 'preferentially-O', 'affect-O', 'amino-O', 'acids-O', 'with-O', 'different-O', 'functions..-O']
['Genomic-O', 'structure-O', 'of-O', 'the-O', 'human-O', 'congenital-B-SpecificDisease', 'chloride-O', 'diarrhea-(CLD)-I-SpecificDisease', 'gene.-O']
['Congenital-B-SpecificDisease', 'chloride-O', 'diarrhea-I-SpecificDisease', '(CLD)-O', 'is-O', 'caused-O', 'by-O', 'mutations-O', 'in-O', 'a-O', 'gene-O', 'which-O', 'encodes-O', 'an-O', 'intestinal-O', 'anion-O', 'transporter.-O']
['We-O', 'report-O', 'here-O', 'the-O', 'complete-O', 'genomic-O', 'organization-O', 'of-O', 'the-O', 'human-O', 'CLD-B-Modifier', 'gene-O', 'which-O', 'spans-O', 'approximately-O', '39kb,-O', 'and-O', 'comprises-O', '21-O', 'exons.-O']
['All-O', 'exon/intron-O', 'boundaries-O', 'conform-O', 'to-O', 'the-O', 'GT/AG-O', 'rule.-O']
['An-O', 'analysis-O', 'of-O', 'the-O', 'putative-O', 'promoter-O', 'region-O', 'sequence-O', 'shows-O', 'a-O', 'putative-O', 'TATA-O', 'box-O', 'and-O', 'predicts-O', 'multiple-O', 'transcription-O', 'factor-O', 'binding-O', 'sites.-O']
['The-O', 'genomic-O', 'structure-O', 'was-O', 'determined-O', 'using-O', 'DNA-O', 'from-O', 'several-O', 'sources-O', 'including-O', 'multiple-O', 'large-insert-O', 'libaries-O', 'and-O', 'genomic-O', 'DNA-O', 'from-O', 'Finnish-O', 'CLD-B-Modifier', 'patients-O', 'and-O', 'controls.-O']
['Exon-specific-O', 'primers-O', 'developed-O', 'in-O', 'this-O', 'study-O', 'will-O', 'facilitate-O', 'mutation-O', 'screening-O', 'studies-O', 'of-O', 'patients-O', 'with-O', 'the-O', 'disease.-O']
['Genomic-O', 'sequencing-O', 'of-O', 'a-O', 'BAC-O', 'clone-O', 'H_RG364P16-O', 'revealed-O', 'the-O', 'presence-O', 'of-O', 'another,-O', 'highly-O', 'homologous-O', 'gene-O', '3-O', 'of-O', 'the-O', 'CLD-O', 'gene,-O', 'with-O', 'a-O', 'similar-O', 'genomic-O', 'structure,-O', 'recently-O', 'identified-O', 'as-O', 'the-O', 'Pendred-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'gene-O', '(PDS)..-O']
['Human-O', 'complement-O', 'factor-O', 'H-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'associated-O', 'with-O', 'hemolytic-B-SpecificDisease', 'uremic-I-SpecificDisease', 'syndrome.-I-SpecificDisease', 'This-O', 'study-O', 'reports-O', 'on-O', 'six-O', 'cases-O', 'of-O', 'deficiency-I-SpecificDisease', 'in-O', 'the-O', 'human-O', 'complement-O', 'regulatory-O', 'protein-O', 'Factor-O', 'H-B-SpecificDisease', '(FH)-O', 'in-O', 'the-O', 'context-O', 'of-O', 'an-O', 'acute-O', 'renal-O', 'disease.-O', 'Five-O', 'of-O', 'the-O', 'cases-O', 'were-O', 'observed-O', 'in-O', 'children-O', 'presenting-O', 'with-O', 'idiopathic-B-SpecificDisease', 'hemolytic-I-SpecificDisease', 'uremic-I-SpecificDisease', 'syndrome-O', '(HUS).-I-SpecificDisease', 'Two-O', 'of-O', 'the-O', 'children-O', 'exhibited-O', 'a-O', 'homozygous-O', 'deficiency-I-SpecificDisease', 'characterized-O', 'by-O', 'the-O', 'absence-O', 'of-O', 'the-O', '150-kD-O', 'form-O', 'of-O', 'Factor-O', 'H-B-SpecificDisease', 'and-O', 'the-O', 'presence,-O', 'upon-O', 'immunoblotting,-O', 'of-O', 'the-O', '42-kD-O', 'Factor-O', 'H-like-O', 'protein-O', '1-O', '(FHL-1)-O', 'and-O', 'other-O', 'FH-related-O', 'protein-O', '(FHR)-O', 'bands.-O']
['Southern-O', 'blot-O', 'and-O', 'PCR-O', 'analysis-O', 'of-O', 'DNA-O', 'of-O', 'one-O', 'patient-O', 'with-O', 'homozygous-O', 'deficiency-O', 'ruled-O', 'out-O', 'the-O', 'presence-O', 'of-O', 'a-O', 'large-O', 'deletion-O', 'of-O', 'the-O', 'FH-B-Modifier', 'gene-O', 'as-O', 'the-O', 'underlying-O', 'defect-O', 'for-O', 'the-O', 'deficiency.-O']
['The-O', 'other-O', 'four-O', 'children-O', 'presented-O', 'with-O', 'heterozygous-O', 'deficiency-O', 'and-O', 'exhibited-O', 'a-O', 'normal-O', 'immunoblotting-O', 'pattern-O', 'of-O', 'proteins-O', 'of-O', 'the-O', 'FH-B-SpecificDisease', 'family.-O']
['Factor-B-SpecificDisease', 'H-I-SpecificDisease', 'deficiency-I-SpecificDisease', 'is-O', 'the-O', 'only-O', 'complement-B-DiseaseClass', 'deficiency-I-DiseaseClass', 'associated-O', 'with-O', 'HUS.-B-SpecificDisease', 'These-O', 'observations-O', 'suggest-O', 'a-O', 'role-O', 'for-O', 'FH-B-SpecificDisease', 'and/or-O', 'FH-B-SpecificDisease', 'receptors-O', 'in-O', 'the-O', 'pathogenesis-O', 'of-O', 'idiopathic-O', 'HUS..-B-SpecificDisease']
['Molecular-O', 'defects-O', 'leading-O', 'to-O', 'human-O', 'complement-O', 'component-O', 'C6-I-SpecificDisease', 'deficiency-I-SpecificDisease', 'in-O', 'an-O', 'African-American-O', 'family.-O']
['Complement-O', 'component-O', 'C6-O', 'deficiency-B-SpecificDisease', '(C6D)-I-SpecificDisease', 'was-O', 'diagnosed-O', 'in-O', 'a-O', '16-year-old-O', 'African-American-O', 'male-O', 'with-O', 'meningococcal-B-SpecificDisease', 'meningitis.-I-SpecificDisease', 'The-O', 'patients-O', 'father-O', 'and-O', 'two-O', 'brothers-O', 'also-O', 'had-O', 'C6D,-I-SpecificDisease', 'but-O', 'gave-O', 'no-O', 'history-O', 'of-O', 'meningitis-O', 'or-O', 'other-O', 'neisserial-O', 'infection.-O', 'By-O', 'using-O', 'exon-specific-O', 'polymerase-O', 'chain-O', 'reaction-O', '(PCR)/single-strand-O', 'conformation-O', 'polymorphism-O', 'as-O', 'a-O', 'screening-O', 'step-O', 'and-O', 'nucleotide-O', 'sequencing-O', 'of-O', 'target-O', 'exons,-O', 'we-O', 'determined-O', 'that-O', 'the-O', 'proband-O', 'was-O', 'a-O', 'compound-O', 'heterozygote-O', 'for-O', 'two-O', 'C6-O', 'gene-O', 'mutations.-O']
['The-O', 'first,-O', '1195delC-O', 'located-O', 'in-O', 'exon-O', '7,-O', 'is-O', 'a-O', 'novel-O', 'mutation,-O', 'while-O', 'the-O', 'second,-O', '1936delG-O', 'in-O', 'exon-O', '12,-O', 'has-O', 'been-O', 'described-O', 'before-O', 'to-O', 'cause-O', 'C6D-B-SpecificDisease', 'in-O', 'an-O', 'unrelated-O', 'African-American-O', 'individual.-O']
['Both-O', 'mutations-O', 'result-O', 'in-O', 'premature-O', 'termination-O', 'codons-O', 'and-O', 'C6-B-SpecificDisease', 'null-O', 'alleles.-O']
['Allele-specific-O', 'PCR-O', 'indicated-O', 'that-O', 'the-O', 'probands-O', 'two-O', 'brothers-O', 'also-O', 'inherited-O', 'the-O', '1195delC-O', 'mutation-O', 'from-O', 'their-O', 'heterozygous-O', 'mother-O', 'and-O', 'the-O', '1936delG-O', 'mutation-O', 'from-O', 'their-O', 'homozygous-O', 'father..-O']
['Hereditary-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'fifth-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'complement-I-SpecificDisease', 'in-O', 'man.-O']
['I.-O']
['Clinical,-O', 'immunochemical,-O', 'and-O', 'family-O', 'studies.-O']
['The-O', 'first-O', 'recognized-O', 'human-O', 'kindred-O', 'with-O', 'hereditary-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'fifth-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'complement-I-SpecificDisease', '(C5)-O', 'is-O', 'described.-O']
['The-O', 'proband,-O', 'a-O', '20-year-old-O', 'black-O', 'female-O', 'with-O', 'systemic-B-SpecificDisease', 'lupus-I-SpecificDisease', 'erythematosus-I-SpecificDisease', 'since-O', 'age-O', '11,-O', 'lacked-O', 'serum-O', 'hemolytic-O', 'complement-O', 'activity,-O', 'even-O', 'during-O', 'remission.-O']
['C5-O', 'was-O', 'undetectable-O', 'in-O', 'her-O', 'serum-O', 'by-O', 'both-O', 'immunodiffusion-O', 'and-O', 'hemolytic-O', 'assays.-O']
['Other-O', 'complement-O', 'components-O', 'were-O', 'normal-O', 'during-O', 'remission-O', 'of-O', 'lupus,-B-SpecificDisease', 'but-O', 'C1,-O', 'C4,-O', 'C2,-O', 'and-O', 'C3-O', 'levels-O', 'fell-O', 'during-O', 'exacerbations.-O']
['A-O', 'younger-O', 'half-sister,-O', 'who-O', 'had-O', 'no-O', 'underlying-O', 'disease,-O', 'was-O', 'also-O', 'found-O', 'to-O', 'lack-O', 'immunochemically-O', 'detectable-O', 'C5.-B-SpecificDisease']
['By-O', 'hemolytic-O', 'assay,-O', 'she-O', 'exhibited-O', '1-2%-O', 'of-O', 'the-O', 'normal-O', 'serum-O', 'C5-O', 'level-O', 'and-O', 'normal-O', 'concentrations-O', 'of-O', 'other-O', 'complement-O', 'components.-O']
['C5-O', 'levels-O', 'of-O', 'other-O', 'family-O', 'members-O', 'were-O', 'either-O', 'normal-O', 'or-O', 'approximately-O', 'half-normal,-O', 'consistent-O', 'with-O', 'autosomal-O', 'codominant-O', 'inheritance-O', 'of-O', 'the-O', 'gene-O', 'determining-O', 'C5-B-SpecificDisease', 'deficiency.-I-SpecificDisease', 'Normal-O', 'hemolytic-O', 'titers-O', 'were-O', 'restored-O', 'to-O', 'both-O', 'homozygous-O', 'C5-deficient-B-Modifier', '(C5D)-O', 'sera-O', 'by-O', 'addition-O', 'of-O', 'highly-O', 'purified-O', 'human-O', 'C5.-O']
['In-O', 'specific-O', 'C5-B-SpecificDisease', 'titrations,-O', 'however,-O', 'it-O', 'was-O', 'noted-O', 'that-O', 'when-O', 'limited-O', 'amounts-O', 'of-O', 'C5-O', 'were-O', 'assayed-O', 'in-O', 'the-O', 'presence-O', 'of-O', 'low-O', 'dilutions-O', 'of-O', 'either-O', 'C5D-B-Modifier', 'serum,-O', 'curving-O', 'rather-O', 'than-O', 'linear-O', 'dose-response-O', 'plots-O', 'were-O', 'consistently-O', 'obtained,-O', 'suggesting-O', 'some-O', 'inhibitory-O', 'effect.-O']
['Further-O', 'studies-O', 'suggested-O', 'that-O', 'low-O', 'dilutions-O', 'of-O', 'C5D-O', 'serum-O', 'contain-O', 'a-O', 'factor-O', '(or-O', 'factors)-O', 'interfering-O', 'at-O', 'some-O', 'step-O', 'in-O', 'the-O', 'hemolytic-O', 'assay-O', 'of-O', 'C5,-O', 'rather-O', 'than-O', 'a-O', 'true-O', 'C5-B-SpecificDisease', 'inhibitor-O', 'or-O', 'inactivator.-O']
['Of-O', 'clinical-O', 'interest-O', 'are-O', '(a)-O', 'the-O', 'documentation-O', 'of-O', 'membranous-B-SpecificDisease', 'glomerulonephritis,-I-SpecificDisease', 'vasculitis,-B-DiseaseClass', 'and-O', 'arthritis-B-DiseaseClass', 'in-O', 'an-O', 'individual-O', 'lacking-O', 'C5-O', '(and-O', 'its-O', 'biologic-O', 'functions),-O', 'and-O', '(b)-O', 'a-O', 'remarkable-O', 'propensity-O', 'to-O', 'bacterial-B-DiseaseClass', 'infections,-I-DiseaseClass', 'in-O', 'the-O', 'proband,-O', 'even-O', 'during-O', 'periods-O', 'of-O', 'low-dose-O', 'or-O', 'alternate-day-O', 'corticosteroid-O', 'therapy.-O']
['Other-O', 'observations-O', 'indicate-O', 'that-O', 'the-O', 'C5D-B-Modifier', 'state-O', 'is-O', 'compatible-O', 'with-O', 'normal-O', 'coagulation-O', 'function-O', 'and-O', 'the-O', 'capacity-O', 'to-O', 'mount-O', 'a-O', 'neutrophilic-O', 'leukocytosis-O', 'during-O', 'pyogenic-B-DiseaseClass', 'infection..-O']
['Cycloheximide-O', 'facilitates-O', 'the-O', 'identification-O', 'of-O', 'aberrant-O', 'transcripts-O', 'resulting-O', 'from-O', 'a-O', 'novel-O', 'splice-site-O', 'mutation-O', 'in-O', 'COL17A1-O', 'in-O', 'a-O', 'patient-O', 'with-O', 'generalized-B-SpecificDisease', 'atrophic-B-SpecificDisease', 'benign-B-SpecificDisease', 'epidermolysis-B-SpecificDisease', 'bullosa.-I-SpecificDisease', 'Patients-O', 'with-O', 'generalized-B-SpecificDisease', 'atrophic-B-SpecificDisease', 'benign-B-SpecificDisease', 'epidermolysis-B-SpecificDisease', 'bullosa-O', 'often-O', 'show-O', 'decreased-O', 'expression-O', 'of-O', 'type-O', 'XVII-O', 'collagen,-O', 'a-O', 'transmembrane-O', 'hemidesmosomal-O', 'protein-O', 'encoded-O', 'by-O', 'COL17A1.-O']
['This-O', 'report-O', 'documents-O', 'a-O', 'novel-O', 'splice-site-O', 'mutation-O', 'in-O', 'COL17A1-O', 'in-O', 'a-O', 'patient-O', 'with-O', 'generalized-B-SpecificDisease', 'atrophic-B-SpecificDisease', 'benign-B-SpecificDisease', 'epidermolysis-B-SpecificDisease', 'bullosa,-I-SpecificDisease', 'and-O', 'applies-O', 'a-O', 'new-O', 'methodology-O', 'to-O', 'define-O', 'and-O', 'characterize-O', 'the-O', 'resulting-O', 'mRNA-O', 'splice-O', 'variants.-O']
['Mutational-O', 'analysis-O', 'of-O', 'COL17A1-O', 'identified-O', 'a-O', 'maternally-O', 'inherited-O', 'G-to-T-O', 'transversion-O', 'at-O', 'the-O', '-1-O', 'position-O', 'of-O', 'exon-O', '32.-O']
['This-O', 'acceptor-O', 'splice-site-O', 'mutation-O', 'led-O', 'to-O', 'the-O', 'formation-O', 'of-O', 'aberrant-O', 'transcripts-O', 'present-O', 'at-O', 'extremely-O', 'low-O', 'levels.-O']
['Based-O', 'on-O', 'our-O', 'recent-O', 'finding-O', 'that-O', 'cycloheximide-O', 'stabilized-O', 'mutant-O', 'COL17A1-B-Modifier', 'transcripts-O', 'in-O', 'keratinocytes-O', 'homozygous-O', 'for-O', 'a-O', 'frameshift-O', 'mutation,-O', 'the-O', 'effects-O', 'of-O', 'the-O', 'splice-site-O', 'mutation-O', 'on-O', 'splicing-O', 'of-O', 'COL17A1-O', 'transcripts-O', 'were-O', 'determined-O', 'using-O', 'reverse-O', 'transcriptase-O', 'polymerase-O', 'chain-O', 'reaction-O', 'of-O', 'total-O', 'RNA-O', 'from-O', 'keratinocytes-O', 'incubated-O', 'for-O', '2.-O']
['5-O', 'h-O', 'in-O', 'the-O', 'presence-O', 'or-O', 'absence-O', 'of-O', '10-O', 'microg-O', 'cycloheximide-O', 'per-O', 'ml.-O']
['Using-O', 'this-O', 'approach,-O', 'an-O', 'abnormally-O', 'spliced-O', 'transcript-O', 'was-O', 'identified-O', 'that-O', 'contains-O', 'an-O', 'extra-O', '264-O', 'bases-O', 'upstream-O', 'from-O', 'exon-O', '32,-O', 'resulting-O', 'in-O', 'a-O', 'premature-O', 'termination-O', 'codon-O', '27-O', 'bp-O', 'downstream-O', 'from-O', 'the-O', 'cryptic-O', 'splice-O', 'site.-O']
['Three-O', 'other-O', 'splice-O', 'variants,-O', 'including-O', 'one-O', 'derived-O', 'from-O', 'the-O', 'skipping-O', 'of-O', 'exon-O', '32,-O', 'were-O', 'also-O', 'identified.-O']
['These-O', 'results-O', 'indicate-O', 'the-O', 'usefulness-O', 'of-O', 'cycloheximide-O', 'treatment-O', 'in-O', 'evaluating-O', 'the-O', 'abnormal-O', 'processing-O', 'of-O', 'mRNA-O', 'due-O', 'to-O', 'splice-site-O', 'mutations,-O', 'because-O', '(i)-O', 'aberrant-O', 'splicing-O', 'often-O', 'generates-O', 'a-O', 'premature-O', 'termination-O', 'codon,-O', '(ii)-O', 'transcripts-O', 'with-O', 'premature-O', 'termination-O', 'codons-O', 'can-O', 'occur-O', 'at-O', 'low-O', 'or-O', 'undetectable-O', 'levels-O', 'due-O', 'to-O', 'nonsense-mediated-O', 'mRNA-O', 'decay,-O', 'and-O', '(iii)-O', 'the-O', 'levels-O', 'of-O', 'these-O', 'transcripts-O', 'can-O', 'be-O', 'increased-O', 'by-O', 'cycloheximide.-O']
['Paternal-O', 'transmission-O', 'of-O', 'congenital-O', 'myotonic-B-SpecificDisease', 'dystrophy.-I-SpecificDisease', 'We-O', 'report-O', 'a-O', 'rare-O', 'case-O', 'of-O', 'paternally-O', 'transmitted-O', 'congenital-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM).-O', 'The-O', 'proband-O', 'is-O', 'a-O', '23-O', 'year-O', 'old,-O', 'mentally-O', 'retarded-O', 'male-O', 'who-O', 'suffers-O', 'severe-O', 'muscular-B-DiseaseClass', 'weakness.-I-DiseaseClass', 'He-O', 'presented-O', 'with-O', 'respiratory-O', 'and-O', 'feeding-O', 'difficulties-O', 'at-O', 'birth.-O']
['His-O', 'two-O', 'sibs-O', 'suffer-O', 'from-O', 'childhood-O', 'onset-O', 'DM.-B-SpecificDisease', 'Their-O', 'late-O', 'father-O', 'had-O', 'the-O', 'adult-O', 'type-O', 'of-O', 'DM,-B-SpecificDisease', 'with-O', 'onset-O', 'around-O', '30-O', 'years.-O']
['Only-O', 'six-O', 'other-O', 'cases-O', 'of-O', 'paternal-O', 'transmission-O', 'of-O', 'congenital-O', 'DM-B-SpecificDisease', 'have-O', 'been-O', 'reported-O', 'recently.-O']
['We-O', 'review-O', 'the-O', 'sex-O', 'related-O', 'effects-O', 'on-O', 'transmission-O', 'of-O', 'congenital-O', 'DM.-B-SpecificDisease', 'Decreased-O', 'fertility-O', 'of-O', 'males-O', 'with-O', 'adult-O', 'onset-O', 'DM-B-SpecificDisease', 'and-O', 'contraction-O', 'of-O', 'the-O', 'repeat-O', 'upon-O', 'male-O', 'transmission-O', 'contribute-O', 'to-O', 'the-O', 'almost-O', 'absent-O', 'occurrence-O', 'of-O', 'paternal-O', 'transmission-O', 'of-O', 'congenital-O', 'DM.-B-SpecificDisease', 'Also-O', 'the-O', 'fathers-O', 'of-O', 'the-O', 'reported-O', 'congenitally-O', 'affected-O', 'children-O', 'showed,-O', 'on-O', 'average,-O', 'shorter-O', 'CTG-O', 'repeat-O', 'lengths-O', 'and-O', 'hence-O', 'less-O', 'severe-O', 'clinical-O', 'symptoms-O', 'than-O', 'the-O', 'mothers-O', 'of-O', 'children-O', 'with-O', 'congenital-O', 'DM.-B-SpecificDisease', 'We-O', 'conclude-O', 'that-O', 'paternal-O', 'transmission-O', 'of-O', 'congenital-O', 'DM-B-SpecificDisease', 'is-O', 'rare-O', 'and-O', 'preferentially-O', 'occurs-O', 'with-O', 'onset-O', 'of-O', 'DM-B-SpecificDisease', 'past-O', '30-O', 'years-O', 'in-O', 'the-O', 'father..-O']
['The-O', 'von-B-Modifier', 'Hippel-Lindau-I-Modifier', 'tumor-I-Modifier', 'suppressor-O', 'gene-O', 'is-O', 'required-O', 'for-O', 'cell-O', 'cycle-O', 'exit-O', 'upon-O', 'serum-O', 'withdrawal.-O']
['The-O', 'inactivation-O', 'of-O', 'the-O', 'von-B-Modifier', 'Hippel-Lindau-I-Modifier', '(VHL)-O', 'tumor-B-Modifier', 'suppressor-O', 'gene-O', 'predisposes-O', 'affected-O', 'individuals-O', 'to-O', 'the-O', 'human-O', 'VHL-B-Modifier', 'cancer-O', 'syndrome-O', 'and-O', 'is-O', 'associated-O', 'with-O', 'sporadic-O', 'renal-B-SpecificDisease', 'cell-I-SpecificDisease', 'carcinomas-I-SpecificDisease', '(RCC)-O', 'and-O', 'brain-O', 'hemangioblastomas.-O', 'VHL-negative-O', '786-0-O', 'RCC-B-SpecificDisease', 'cells-O', 'are-O', 'tumorigenic-O', 'in-O', 'nude-O', 'mice-O', 'which-O', 'is-O', 'suppressed-O', 'by-O', 'the-O', 'reintroduction-O', 'of-O', 'VHL.-O', 'Remarkably,-O', 'this-O', 'occurs-O', 'without-O', 'affecting-O', 'the-O', 'growth-O', 'rate-O', 'and-O', 'cell-O', 'cycle-O', 'profile-O', 'of-O', 'these-O', 'cells-O', 'in-O', 'culture.-O']
['The-O', '786-0-O', 'cell-O', 'line,-O', 'like-O', 'many-O', 'cancer-B-DiseaseClass', 'cells,-O', 'fails-O', 'to-O', 'exit-O', 'the-O', 'cell-O', 'cycle-O', 'upon-O', 'serum-O', 'withdrawal.-O']
['Here,-O', 'it-O', 'is-O', 'shown-O', 'that-O', 'reintroduction-O', 'of-O', 'the-O', 'wild-type-O', 'VHL-B-Modifier', 'gene-O', 'restores-O', 'the-O', 'ability-O', 'of-O', 'VHL-negative-O', 'RCC-B-Modifier', 'cancer-O', 'cells-O', 'to-O', 'exit-O', 'the-O', 'cell-O', 'cycle-O', 'and-O', 'enter-O', 'G0/quiescence-O', 'in-O', 'low-O', 'serum.-O']
['Both-O', 'VHL-positive-B-Modifier', 'and-O', 'VHL-negative-B-Modifier', 'RCC-B-SpecificDisease', 'cells-O', 'exit-O', 'the-O', 'cell-O', 'cycle-O', 'by-O', 'contact-O', 'inhibition.-O']
['The-O', 'cyclin-dependent-O', 'kinase-O', 'inhibitor,-O', 'p27,-O', 'accumulates-O', 'upon-O', 'serum-O', 'withdrawal,-O', 'only-O', 'in-O', 'the-O', 'presence-O', 'of-O', 'VHL-B-Modifier', 'as-O', 'a-O', 'result-O', 'of-O', 'the-O', 'stabilization-O', 'of-O', 'the-O', 'protein.-O']
['We-O', 'propose-O', 'that-O', 'the-O', 'loss-O', 'of-O', 'wild-type-O', 'VHL-O', 'gene-O', 'results-O', 'in-O', 'a-O', 'specific-O', 'cellular-O', 'defect-O', 'in-O', 'serum-dependent-O', 'growth-O', 'control,-O', 'which-O', 'may-O', 'initiate-O', 'tumor-B-Modifier', 'formation.-O']
['This-O', 'is-O', 'corrected-O', 'by-O', 'the-O', 'reintroduction-O', 'of-O', 'wild-type-O', 'VHL,-O', 'implicating-O', 'VHL-B-Modifier', 'as-O', 'the-O', 'first-O', 'tumor-B-Modifier', 'suppressor-O', 'involved-O', 'in-O', 'the-O', 'regulation-O', 'of-O', 'cell-O', 'cycle-O', 'exit,-O', 'which-O', 'is-O', 'consistent-O', 'with-O', 'its-O', 'gatekeeper-O', 'function-O', 'in-O', 'the-O', 'kidney..-O']
['Stable-O', 'interaction-O', 'between-O', 'the-O', 'products-O', 'of-O', 'the-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'tumor-B-Modifier', 'suppressor-O', 'genes-O', 'in-O', 'mitotic-O', 'and-O', 'meiotic-O', 'cells.-O']
['BRCA1-O', 'and-O', 'BRCA2-O', 'account-O', 'for-O', 'most-O', 'cases-O', 'of-O', 'familial-B-DiseaseClass', 'early-O', 'onset-O', 'breast-B-SpecificDisease', 'and/or-I-SpecificDisease', 'ovarian-I-SpecificDisease', 'cancer-I-SpecificDisease', 'and-O', 'encode-O', 'products-O', 'that-O', 'each-O', 'interact-O', 'with-O', 'hRAD51.-O']
['Results-O', 'presented-O', 'here-O', 'show-O', 'that-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'coexist-O', 'in-O', 'a-O', 'biochemical-O', 'complex-O', 'and-O', 'colocalize-O', 'in-O', 'subnuclear-O', 'foci-O', 'in-O', 'somatic-O', 'cells-O', 'and-O', 'on-O', 'the-O', 'axial-O', 'elements-O', 'of-O', 'developing-O', 'synaptonemal-O', 'complexes.-O']
['Like-O', 'BRCA1-O', 'and-O', 'RAD51,-O', 'BRCA2-O', 'relocates-O', 'to-O', 'PCNA-O', '+-O', 'replication-O', 'sites-O', 'following-O', 'exposure-O', 'of-O', 'S-O', 'phase-O', 'cells-O', 'to-O', 'hydroxyurea-O', 'or-O', 'UV-O', 'irradiation.-O']
['Thus,-O', 'BRCA1-O', 'and-O', 'BRCA2-O', 'participate,-O', 'together,-O', 'in-O', 'a-O', 'pathway-O', '(s)-O', 'associated-O', 'with-O', 'the-O', 'activation-O', 'of-O', 'double-strand-O', 'break-O', 'repair-O', 'and/or-O', 'homologous-O', 'recombination.-O']
['Dysfunction-O', 'of-O', 'this-O', 'pathway-O', 'may-O', 'be-O', 'a-O', 'general-O', 'phenomenon-O', 'in-O', 'the-O', 'majority-O', 'of-O', 'cases-O', 'of-O', 'hereditary-B-CompositeMention', 'breast-I-CompositeMention', 'and/or-I-CompositeMention', 'ovarian-I-CompositeMention', 'cancer..-I-CompositeMention']
['BRCA1-O', 'required-O', 'for-O', 'transcription-coupled-O', 'repair-O', 'of-O', 'oxidative-O', 'DNA-O', 'damage.-O']
['The-O', 'breast-B-Modifier', 'and-I-Modifier', 'ovarian-I-Modifier', 'cancer-I-Modifier', 'susceptibility-O', 'gene-O', 'BRCA1-O', 'encodes-O', 'a-O', 'zinc-O', 'finger-O', 'protein-O', 'of-O', 'unknown-O', 'function.-O']
['Association-O', 'of-O', 'the-O', 'BRCA1-O', 'protein-O', 'with-O', 'the-O', 'DNA-O', 'repair-O', 'protein-O', 'Rad51-O', 'and-O', 'changes-O', 'in-O', 'the-O', 'phosphorylation-O', 'and-O', 'cellular-O', 'localization-O', 'of-O', 'the-O', 'protein-O', 'after-O', 'exposure-O', 'to-O', 'DNA-damaging-O', 'agents-O', 'are-O', 'consistent-O', 'with-O', 'a-O', 'role-O', 'for-O', 'BRCA1-O', 'in-O', 'DNA-O', 'repair.-O']
['Here,-O', 'it-O', 'is-O', 'shown-O', 'that-O', 'mouse-O', 'embryonic-O', 'stem-O', 'cells-O', 'deficient-O', 'in-O', 'BRCA1-O', 'are-O', 'defective-O', 'in-O', 'the-O', 'ability-O', 'to-O', 'carry-O', 'out-O', 'transcription-coupled-O', 'repair-O', 'of-O', 'oxidative-O', 'DNA-O', 'damage,-O', 'and-O', 'are-O', 'hypersensitive-O', 'to-O', 'ionizing-O', 'radiation-O', 'and-O', 'hydrogen-O', 'peroxide.-O']
['These-O', 'results-O', 'suggest-O', 'that-O', 'BRCA1-O', 'participates,-O', 'directly-O', 'or-O', 'indirectly,-O', 'in-O', 'transcription-coupled-O', 'repair-O', 'of-O', 'oxidative-O', 'DNA-O', 'damage..-O']
['Inherited-O', 'colorectal-B-SpecificDisease', 'polyposis-I-SpecificDisease', 'and-O', 'cancer-I-SpecificDisease', 'risk-O', 'of-O', 'the-O', 'APC-B-Modifier', 'I1307K-O', 'polymorphism.-O']
['Germ-line-O', 'and-O', 'somatic-O', 'truncating-O', 'mutations-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'are-O', 'thought-O', 'to-O', 'initiate-O', 'colorectal-B-SpecificDisease', 'tumor-I-SpecificDisease', 'formation-O', 'in-O', 'familial-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', 'syndrome-O', 'and-O', 'sporadic-O', 'colorectal-B-SpecificDisease', 'carcinogenesis,-O', 'respectively.-O']
['Recently,-O', 'an-O', 'isoleucine--O', '>-O', 'lysine-O', 'polymorphism-O', 'at-O', 'codon-O', '1307-O', '(I1307K)-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'has-O', 'been-O', 'identified-O', 'in-O', '6%-O', '-7%-O', 'of-O', 'the-O', 'Ashkenazi-O', 'Jewish-O', 'population.-O']
['To-O', 'assess-O', 'the-O', 'risk-O', 'of-O', 'this-O', 'common-O', 'APC-B-Modifier', 'allelic-O', 'variant-O', 'in-O', 'colorectal-B-SpecificDisease', 'carcinogenesis,-O', 'we-O', 'have-O', 'analyzed-O', 'a-O', 'large-O', 'cohort-O', 'of-O', 'unselected-O', 'Ashkenazi-O', 'Jewish-O', 'subjects-O', 'with-O', 'adenomatous-B-Modifier', 'polyps-I-Modifier', 'and-O']
['or-O', 'colorectal-B-SpecificDisease', 'cancer,-I-SpecificDisease', 'for-O', 'the-O', 'APC-B-Modifier', 'I1307K-O', 'polymorphism.-O']
['The-O', 'APC-B-Modifier', 'I1307K-O', 'allele-O', 'was-O', 'identified-O', 'in-O', '48-O', '(10.-O']
['1%)-O', 'of-O', '476-O', 'patients.-O']
['Compared-O', 'with-O', 'the-O', 'frequency-O', 'in-O', 'two-O', 'separate-O', 'population-O', 'control-O', 'groups,-O', 'the-O', 'APC-B-Modifier', 'I1307K-O', 'allele-O', 'is-O', 'associated-O', 'with-O', 'an-O', 'estimated-O', 'relative-O', 'risk-O', 'of-O', '1.-O']
['5-1.-O']
['7-O', 'for-O', 'colorectal-B-SpecificDisease', 'neoplasia-O', '(both-O', 'P-O', '=.01).-O', 'Furthermore,-O', 'compared-O', 'with-O', 'noncarriers,-O', 'APC-B-Modifier', 'I1307K-O', 'carriers-O', 'had-O', 'increased-O', 'numbers-O', 'of-O', 'adenomas-B-DiseaseClass', 'and-O', 'colorectal-B-SpecificDisease', 'cancers-I-SpecificDisease', 'per-O', 'patient-O', '(P-O', '=.03),-O', 'as-O', 'well-O', 'as-O', 'a-O', 'younger-O', 'age-O', 'at-O', 'diagnosis.-O']
['We-O', 'conclude-O', 'that-O', 'the-O', 'APC-B-Modifier', 'I1307K-O', 'variant-O', 'leads-O', 'to-O', 'increased-O', 'adenoma-B-CompositeMention', 'formation-O', 'and-O', 'directly-O', 'contributes-O', 'to-O', '3%-O', '-4%-O', 'of-O', 'all-O', 'Ashkenazi-O', 'Jewish-O', 'colorectal-B-SpecificDisease', 'cancer.-I-SpecificDisease', 'The-O', 'estimated-O', 'relative-O', 'risk-O', 'for-O', 'carriers-O', 'may-O', 'justify-O', 'specific-O', 'clinical-O', 'screening-O', 'for-O', 'the-O', '360,-O', '000-O', 'Americans-O', 'expected-O', 'to-O', 'harbor-O', 'this-O', 'allele,-O', 'and-O', 'genetic-O', 'testing-O', 'in-O', 'the-O', 'setting-O', 'of-O', 'long-term-outcome-O', 'studies-O', 'may-O', 'impact-O', 'significantly-O', 'on-O', 'colorectal-B-SpecificDisease', 'cancer-O', 'prevention-O', 'in-O', 'this-O', 'population.-O']
['ATM-O', 'mutations-O', 'and-O', 'phenotypes-O', 'in-O', 'ataxia-telangiectasia-B-SpecificDisease', 'families-O', 'in-O', 'the-O', 'British-O', 'Isles:-O', 'expression-O', 'of-O', 'mutant-O', 'ATM-O', 'and-O', 'the-O', 'risk-O', 'of-O', 'leukemia,-B-DiseaseClass', 'lymphoma,-I-DiseaseClass', 'and-O', 'breast-B-DiseaseClass', 'cancer.-O', 'We-O', 'report-O', 'the-O', 'spectrum-O', 'of-O', '59-O', 'ATM-O', 'mutations-O', 'observed-O', 'in-O', 'ataxia-telangiectasia-B-SpecificDisease', '(A-T)-O', 'patients-O', 'in-O', 'the-O', 'British-O', 'Isles.-O']
['Of-O', '51-O', 'ATM-O', 'mutations-O', 'identified-O', 'in-O', 'families-O', 'native-O', 'to-O', 'the-O', 'British-O', 'Isles,-O', '11-O', 'were-O', 'founder-O', 'mutations,-O', 'and-O', '2-O', 'of-O', 'these-O', '11-O', 'conferred-O', 'a-O', 'milder-O', 'clinical-O', 'phenotype-O', 'with-O', 'respect-O', 'to-O', 'both-O', 'cerebellar-B-DiseaseClass', 'degeneration-I-DiseaseClass', 'and-O', 'cellular-O', 'features.-O']
['We-O', 'report,-O', 'in-O', 'two-O', 'A-T-B-SpecificDisease', 'families,-O', 'an-O', 'ATM-O', 'mutation-O', '(7271T--O', '>O', 'G)-O', 'that-O', 'may-O', 'be-O', 'associated-O', 'with-O', 'an-O', 'increased-O', 'risk-O', 'of-O', 'breast-B-SpecificDisease', 'cancer-I-SpecificDisease', 'in-O', 'both-O', 'homozygotes-O', 'and-O', 'heterozygotes-O', '(relative-O', 'risk-O', '12.-O']
['7;-O', 'P-O', '=.-O', '0025),-O', 'although-O', 'there-O', 'is-O', 'a-O', 'less-O', 'severe-O', 'A-T-B-Modifier', 'phenotype-O', 'in-O', 'terms-O', 'of-O', 'the-O', 'degree-O', 'of-O', 'cerebellar-B-DiseaseClass', 'degeneration.-I-DiseaseClass', 'This-O', 'mutation-O', '(7271T--O', '>-O', 'G)-O', 'also-O', 'allows-O', 'expression-O', 'of-O', 'full-length-O', 'ATM-O', 'protein-O', 'at-O', 'a-O', 'level-O', 'comparable-O', 'with-O', 'that-O', 'in-O', 'unaffected-O', 'individuals.-O']
['In-O', 'addition,-O', 'we-O', 'have-O', 'studied-O', '18-O', 'A-T-B-SpecificDisease', 'patients,-I-SpecificDisease', 'in-O', '15-O', 'families,-O', 'who-O', 'developed-O', 'leukemia,-I-SpecificDisease', 'lymphoma,-I-SpecificDisease', 'preleukemic-O', 'T-cell-O', 'proliferation,-O', 'or-O', 'Hodgkin-B-SpecificDisease', 'lymphoma,-I-SpecificDisease', 'mostly-O', 'in-O', 'childhood.-O']
['A-O', 'wide-O', 'variety-O', 'of-O', 'ATM-O', 'mutation-O', 'types,-O', 'including-O', 'missense-O', 'mutations-O', 'and-O', 'in-frame-O', 'deletions,-O', 'were-O', 'seen-O', 'in-O', 'these-O', 'patients.-O']
['We-O', 'also-O', 'show-O', 'that-O', '25%-O', 'of-O', 'all-O', 'A-T-B-Modifier', 'patients-O', 'carried-O', 'in-frame-O', 'deletions-O', 'or-O', 'missense-O', 'mutations,-O', 'many-O', 'of-O', 'which-O', 'were-O', 'also-O', 'associated-O', 'with-O', 'expression-O', 'of-O', 'mutant-O', 'ATM-O', 'protein.-O']
['Prevalence-O', 'of-O', 'the-O', 'I1307K-O', 'APC-O', 'gene-O', 'variant-O', 'in-O', 'Israeli-O', 'Jews-O', 'of-O', 'differing-O', 'ethnic-O', 'origin-O', 'and-O', 'risk-O', 'for-O', 'colorectal-B-SpecificDisease', 'cancer.-I-SpecificDisease', 'BACKGROUND-O', '&-O', 'AIMS-O', 'Israeli-O', 'Jews-O', 'of-O', 'European-O', 'birth,-O', 'i.-O']
['e.,-O', 'Ashkenazim,-O', 'have-O', 'the-O', 'highest-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'incidence-O', 'of-O', 'any-O', 'Israeli-O', 'ethnic-O', 'group.-O']
['The-O', 'I1307K-O', 'APC-B-Modifier', 'gene-O', 'variant-O', 'was-O', 'found-O', 'in-O', '6.-O']
['1%-O', 'of-O', 'American-O', 'Jews,-O', '28%-O', 'of-O', 'their-O', 'familial-B-Modifier', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'cases,-O', 'but-O', 'not-O', 'in-O', 'non-Jews.-O']
['We-O', 'assessed-O', 'the-O', 'I1307K-O', 'prevalence-O', 'in-O', 'Israeli-O', 'Jews-O', 'of-O', 'differing-O', 'ethnic-O', 'origin-O', 'and-O', 'risk-O', 'for-O', 'colorectal-B-Modifier', 'cancer-I-Modifier', '.', 'METHODS-O', 'DNA-O', 'samples-O', 'from-O', '500-O', 'unrelated-O', 'Jews-O', 'of-O', 'European-O', 'or-O', 'non-European-O', 'origin,-O', 'with-O', 'or-O', 'without-O', 'a-O', 'personal-O', 'and/or-O', 'family-O', 'history-O', 'of-O', 'neoplasia,-O', 'were-O', 'examined-O', 'for-O', 'the-O', 'I1307K-O', 'variant-O', 'by-O', 'the-O', 'allele-specific-O', 'oligonucleotide-O', '(ASO)-O', 'method.-O']
['RESULTS-O', 'In-O', 'persons-O', 'at-O', 'average-O', 'risk-O', 'for-O', 'colorectal-B-SpecificDisease', 'cancer,-I-SpecificDisease', 'I1307K-O', 'was-O', 'found-O', 'in-O', '5.-O']
['0%-O', 'of-O', '120-O', 'European-O', 'and-O', '1.-O']
['6%-O', 'of-O', '188-O', 'non-European-O', 'Jews-O', '(P-O', '=O', '0.-O']
['08).-O', 'It-O', 'occurred-O', 'in-O', '15.-O']
['4%-O', 'of-O', '52-O', 'Ashkenazi-O', 'Israelis-O', 'with-O', 'familial-B-SpecificDisease', 'cancer-I-SpecificDisease', '(P-O', '=O', '0.-O']
['02)-O', 'and-O', 'was-O', 'not-O', 'detected-O', 'in-O', '51-O', 'non-European-O', 'Jews-O', 'at-O', 'increased-O', 'cancer-B-DiseaseClass', 'risk.-O']
['Colorectal-B-SpecificDisease', 'neoplasia-O', 'occurred-O', 'personally-O', 'or-O', 'in-O', 'the-O', 'families-O', 'of-O', '13-O', 'of-O', '20-O', 'Ashkenazi-O', 'I1307K-O', 'carriers,-O', '8-O', 'of-O', 'whom-O', 'also-O', 'had-O', 'a-O', 'personal-O', 'or-O', 'family-O', 'history-O', 'of-O', 'noncolonic-O', 'neoplasia.-O', 'CONCLUSIONS-O', 'The-O', 'I1307K-O', 'APC-B-Modifier', 'variant-O', 'may-O', 'represent-O', 'a-O', 'susceptibility-O', 'gene-O', 'for-O', 'colorectal,-O', 'or-O', 'other,-O', 'cancers-I-SpecificDisease', 'in-O', 'Ashkenazi-O', 'Jews,-O', 'and-O', 'partially-O', 'explains-O', 'the-O', 'higher-O', 'incidence-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'in-O', 'European-O', 'Israelis.-O']
['Systematic-O', 'analysis-O', 'of-O', 'coproporphyrinogen-O', 'oxidase-O', 'gene-O', 'defects-O', 'in-O', 'hereditary-B-SpecificDisease', 'coproporphyria-I-SpecificDisease', 'and-O', 'mutation-O', 'update.-O']
['Hereditary-B-DiseaseClass', 'coproporphyria-B-SpecificDisease', '(HC)-O', 'is-O', 'an-O', 'acute-O', 'hepatic-O', 'porphyria-B-DiseaseClass', 'with-O', 'autosomal-B-DiseaseClass', 'dominant-I-DiseaseClass', 'inheritance-O', 'caused-O', 'by-O', 'deficient-O', 'activity-O', 'of-O', 'coproporphyrinogen-O', 'III-O', 'oxidase-O', '(CPO).-O', 'Clinical-O', 'manifestations-O', 'of-O', 'the-O', 'disease-O', 'are-O', 'characterized-O', 'by-O', 'acute-O', 'attacks-O', 'of-O', 'neurological-B-DiseaseClass', 'dysfunction-O', 'often-O', 'precipitated-O', 'by-O', 'drugs,-O', 'fasting,-O', 'cyclical-O', 'hormonal-O', 'changes,-O', 'or-O', 'infectious-O', 'diseases.-O', 'Skin-O', 'photosensitivity-O', 'may-O', 'also-O', 'be-O', 'present.-O']
['The-O', 'seven-O', 'exons,-O', 'the-O', 'exon/intron-O', 'boundaries-O', 'and-O', 'part-O', 'of-O', '3-O', 'noncoding-O', 'sequence-O', 'of-O', 'the-O', 'CPO-O', 'gene-O', 'were-O', 'systematically-O', 'analyzed-O', 'by-O', 'an-O', 'exon-by-exon-O', 'denaturing-O', 'gradient-O', 'gel-O', 'electrophoresis-O', '(DGGE)-O', 'strategy-O', 'followed-O', 'by-O', 'direct-O', 'sequencing-O', 'in-O', 'seven-O', 'unrelated-O', 'heterozygous-O', 'HC-B-Modifier', 'patients-O', 'from-O', 'France,-O', 'Holland,-O', 'and-O', 'Czech-O', 'Republic.-O']
['Seven-O', 'novel-O', 'mutations-O', 'and-O', 'two-O', 'new-O', 'polymorphisms-O', 'were-O', 'detected.-O']
['Among-O', 'these-O', 'mutations-O', 'two-O', 'are-O', 'missense-O', '(G197W,-O', 'W427R),-O', 'two-O', 'are-O', 'nonsense-O', '(Q306X,-O', 'Q385X),-O', 'two-O', 'are-O', 'small-O', 'deletions-O', '(662de14bp;-O', '1168del3bp-O', 'removing-O', 'a-O', 'glycine-O', 'at-O', 'position-O', '390),-O', 'and-O', 'one-O', 'is-O', 'a-O', 'splicing-O', 'mutation-O', '(IVS1-15c--O', '>-O', 'g)-O', 'which-O', 'creates-O', 'a-O', 'new-O', 'acceptor-O', 'splice-O', 'site.-O']
['The-O', 'pathological-O', 'significance-O', 'of-O', 'the-O', 'point-O', 'mutations-O', 'G197W,-O', 'W427R,-O', 'and-O', 'the-O', 'in-frame-O', 'deletion-O', '390delGly-O', 'were-O', 'assessed-O', 'by-O', 'their-O', 'respective-O', 'expression-O', 'in-O', 'a-O', 'prokaryotic-O', 'system-O', 'using-O', 'site-directed-O', 'mutagenesis.-O']
['These-O', 'mutations-O', 'resulted-O', 'in-O', 'the-O', 'absence-O', 'or-O', 'a-O', 'dramatic-O', 'decrease-O', 'of-O', 'CPO-O', 'activity.-O']
['The-O', 'two-O', 'polymorphisms-O', 'were-O', 'localized-O', 'in-O', 'noncoding-O', 'part-O', 'of-O', 'the-O', 'gene-O', '1)-O', 'a-O', 'C/G-O', 'polymorphism-O', 'in-O', 'the-O', 'promotor-O', 'region,-O', '142-O', 'bp-O', 'upstream-O', 'from-O', 'the-O', 'transcriptional-O', 'initiation-O', 'site-O', '(-142C/G),-O', 'and-O', '2)-O', 'a-O', '6-O', 'bp-O', 'deletion-O', 'polymorphism-O', 'in-O', 'the-O', '3-O', 'noncoding-O', 'part-O', 'of-O', 'the-O', 'CPO-O', 'gene,-O', '574-O', 'bp-O', 'downstream-O', 'of-O', 'the-O', 'last-O', 'base-O', 'of-O', 'the-O', 'normal-O', 'termination-O', 'codon-O', '(+-O', '574-O', 'delATTCTT).-O', 'Five-O', 'intragenic-O', 'dimorphisms-O', 'are-O', 'now-O', 'well-O', 'characterized-O', 'and-O', 'the-O', 'high-O', 'degree-O', 'of-O', 'allelic-O', 'heterogeneity-O', 'in-O', 'HC-O', 'is-O', 'demonstrated-O', 'with-O', 'seven-O', 'new-O', 'different-O', 'mutations-O', 'making-O', 'a-O', 'total-O', 'of-O', 'nineteen-O', 'CPO-O', 'gene-O', 'defects-O', 'reported-O', 'so-O', 'far..-O']
['Disruption-O', 'of-O', 'splicing-O', 'regulated-O', 'by-O', 'a-O', 'CUG-binding-O', 'protein-O', 'in-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM)-O', 'is-O', 'caused-O', 'by-O', 'a-O', 'CTG-O', 'expansion-O', 'in-O', 'the-O', '3-O', 'untranslated-O', 'region-O', 'of-O', 'the-O', 'DM-B-Modifier', 'gene.-O']
['One-O', 'model-O', 'of-O', 'DM-B-Modifier', 'pathogenesis-O', 'suggests-O', 'that-O', 'RNAs-O', 'from-O', 'the-O', 'expanded-O', 'allele-O', 'create-O', 'a-O', 'gain-of-function-O', 'mutation-O', 'by-O', 'the-O', 'inappropriate-O', 'binding-O', 'of-O', 'proteins-O', 'to-O', 'the-O', 'CUG-O', 'repeats.-O']
['Data-O', 'presented-O', 'here-O', 'indicate-O', 'that-O', 'the-O', 'conserved-O', 'heterogeneous-O', 'nuclear-O', 'ribonucleoprotein,-O', 'CUG-binding-O', 'protein-O', '(CUG-BP),-O', 'may-O', 'mediate-O', 'the-O', 'trans-dominant-O', 'effect-O', 'of-O', 'the-O', 'RNA.-O']
['CUG-BP-O', 'was-O', 'found-O', 'to-O', 'bind-O', 'to-O', 'the-O', 'human-O', 'cardiac-O', 'troponin-O', 'T-O', '(cTNT)-O', 'pre-messenger-O', 'RNA-O', 'and-O', 'regulate-O', 'its-O', 'alternative-O', 'splicing.-O']
['Splicing-O', 'of-O', 'cTNT-O', 'was-O', 'disrupted-O', 'in-O', 'DM-B-Modifier', 'striated-O', 'muscle-O', 'and-O', 'in-O', 'normal-O', 'cells-O', 'expressing-O', 'transcripts-O', 'that-O', 'contain-O', 'CUG-O', 'repeats.-O']
['Altered-O', 'expression-O', 'of-O', 'genes-O', 'regulated-O', 'posttranscriptionally-O', 'by-O', 'CUG-BP-O', 'therefore-O', 'may-O', 'contribute-O', 'to-O', 'DM-B-Modifier', 'pathogenesis..-O']
['Complement-B-SpecificDisease', 'C7-I-SpecificDisease', 'deficiency:-I-SpecificDisease', 'seven-O', 'further-O', 'molecular-O', 'defects-O', 'and-O', 'their-O', 'associated-O', 'marker-O', 'haplotypes.-O']
['Seven-O', 'further-O', 'molecular-O', 'bases-O', 'of-O', 'C7-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'are-O', 'described.-O']
['All-O', 'these-O', 'new-O', 'molecular-O', 'defects-O', 'involve-O', 'single-nucleotide-O', 'events,-O', 'deletions-O', 'and-O', 'substitutions,-O', 'some-O', 'of-O', 'which-O', 'alter-O', 'splice-O', 'sites,-O', 'and-O', 'others-O', 'codons.-O']
['They-O', 'are-O', 'distributed-O', 'along-O', 'the-O', 'C7-B-SpecificDisease', 'gene,-O', 'but-O', 'predominantly-O', 'towards-O', 'the-O', '3-O', 'end.-O']
['All-O', 'were-O', 'found-O', 'in-O', 'compound-O', 'heterozygous-O', 'individuals.-O']
['The-O', 'C6/C7-B-CompositeMention', 'marker-O', 'haplotypes-O', 'associated-O', 'with-O', 'most-O', 'C7-B-SpecificDisease', 'defects-I-SpecificDisease', 'are-O', 'tabulated..-O']
['A-O', 'Japanese-O', 'family-O', 'with-O', 'adrenoleukodystrophy-B-SpecificDisease', 'with-O', 'a-O', 'codon-O', '291-O', 'deletion:-O', 'a-O', 'clinical,-O', 'biochemical,-O', 'pathological,-O', 'and-O', 'genetic-O', 'report.-O']
['We-O', 'report-O', 'a-O', 'Japanese-O', 'family-O', 'with-O', 'adrenoleukodystrophy-B-SpecificDisease', '(ALD)-O', 'with-O', 'a-O', 'three-O', 'base-O', 'pair-O', 'deletion-O', '(delGAG-O', '291)-O', 'in-O', 'the-O', 'ALD-B-Modifier', 'gene.-O']
['A-O', 'variety-O', 'of-O', 'phenotypes-O', 'were-O', 'observed-O', 'within-O', 'this-O', 'family.-O']
['While-O', 'the-O', 'proband-O', '(patient-O', '1)-O', 'was-O', 'classified-O', 'as-O', 'having-O', 'a-O', 'rare-O', 'intermediate-O', 'type-O', 'of-O', 'adult-O', 'cerebral-B-SpecificDisease', 'and-O', 'cerebello-brain-O', 'stem-O', 'forms,-O', 'his-O', 'younger-O', 'brother-O', '(patient-O', '2)-O', 'and-O', 'nephew-O', '(patient-O', '3)-O', 'had-O', 'a-O', 'childhood-B-SpecificDisease', 'ALD-I-SpecificDisease', 'type.-O']
['Another-O', 'nephew-O', '(patient-O', '4)-O', 'of-O', 'patient-O', '1-O', 'was-O', 'classified-O', 'as-O', 'having-O', 'an-O', 'adolescent-B-SpecificDisease', 'form.-I-SpecificDisease']
['The-O', 'tau-O', 'level-O', 'in-O', 'the-O', 'cerebrospinal-O', 'fluid-O', '(CSF)-O', 'in-O', 'patient-O', '1-O', 'was-O', 'as-O', 'high-O', 'as-O', 'that-O', 'of-O', 'patients-O', 'with-O', 'Alzheimers-B-SpecificDisease', 'disease-O', '(AD).-O', 'His-O', 'brain-O', 'magnetic-O', 'resonance-O', 'image-O', '(MRI)-O', 'showed-O', 'abnormalities-O', 'in-O', 'the-O', 'bilateral-O', 'cerebellar-O', 'hemispheres-O', 'and-O', 'brain-O', 'stem,-O', 'but-O', 'not-O', 'in-O', 'the-O', 'cerebral-O', 'white-O', 'matter,-O', 'where-O', 'marked-O', 'reductions-O', 'of-O', 'the-O', 'cerebral-O', 'blood-O', 'flow-O', 'and-O', 'oxygen-O', 'metabolism-O', 'were-O', 'clearly-O', 'demonstrated-O', 'by-O', 'positron-O', 'emission-O', 'tomography-O', '(PET).-O', 'In-O', 'patients-O', '2-O', 'and-O', '3,-O', 'the-O', 'autopsy-O', 'findings-O', 'showed-O', 'massive-O', 'demyelination-O', 'of-O', 'the-O', 'cerebral-O', 'white-O', 'matter-O', 'with-O', 'sparing-O', 'of-O', 'the-O', 'U-fibers,-O', 'compatible-O', 'with-O', 'the-O', 'findings-O', 'of-O', 'childhood-O', 'ALD.-O', 'Oleic-O', 'and-O', 'erucic-O', 'acids-O', '(Lorenzos-O', 'Oil)-O', 'were-O', 'administered-O', 'to-O', 'patients-O', '1-O', 'and-O', '4,-O', 'but-O', 'sufficient-O', 'effectiveness-O', 'was-O', 'not-O', 'obtained.-O']
['The-O', 'findings-O', 'in-O', 'this-O', 'family-O', 'suggest-O', 'that-O', 'delGAG291-O', 'is-O', 'part-O', 'of-O', 'the-O', 'cause-O', 'of-O', 'Japanese-O', 'ALD-B-SpecificDisease', 'with-O', 'phenotypic-O', 'variations.-O']
['Moreover,-O', 'although-O', 'the-O', 'scale-O', 'of-O', 'the-O', 'study-O', 'is-O', 'limited,-O', 'there-O', 'is-O', 'a-O', 'possibility-O', 'that-O', 'PET-O', 'can-O', 'detect-O', 'an-O', 'insidious-O', 'lesion-O', 'which-O', 'is-O', 'undetectable-O', 'by-O', 'computed-O', 'tomogram-O', '(CT)-O', 'or-O', 'MRI-O', 'analysis,-O', 'and-O', 'that-O', 'the-O', 'higher-O', 'level-O', 'of-O', 'tau-O', 'reflects-O', 'the-O', 'process-O', 'of-O', 'neuronal-O', 'degeneration-O', 'in-O', 'ALD.-B-SpecificDisease', 'Lorenzos-O', 'Oil-O', 'should-O', 'be-O', 'given-O', 'in-O', 'the-O', 'early-O', 'stage..-O']
['Further-O', 'evidence-O', 'for-O', 'a-O', 'major-O', 'ancient-O', 'mutation-O', 'underlying-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', 'from-O', 'linkage-O', 'disequilibrium-O', 'studies-O', 'in-O', 'the-O', 'Japanese-O', 'population.-O']
['The-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM)-O', 'mutation-O', 'is-O', 'an-O', 'unstable-O', '(CTG)-O', 'n-O', 'repeat,-O', 'present-O', 'at-O', 'a-O', 'copy-O', 'number-O', 'of-O', '5-37-O', 'repeats-O', 'on-O', 'normal-O', 'chromosomes-O', 'but-O', 'amplified-O', 'to-O', '50-3000-O', 'copies-O', 'on-O', 'DM-B-Modifier', 'chromosomes.-O']
['Previous-O', 'findings-O', 'in-O', 'Caucasian-O', 'populations-O', 'of-O', 'a-O', 'DM-B-Modifier', 'founder-O', 'chromosome-O', 'raise-O', 'a-O', 'question-O', 'about-O', 'the-O', 'molecular-O', 'events-O', 'involved-O', 'in-O', 'the-O', 'expansion-O', 'mutation.-O']
['To-O', 'investigate-O', 'whether-O', 'a-O', 'founder-O', 'chromosome-O', 'for-O', 'the-O', 'DM-B-Modifier', 'mutation-O', 'exists-O', 'in-O', 'the-O', 'Japanese-O', 'population,-O', 'we-O', 'genotyped-O', 'families-O', 'using-O', 'polymorphic-O', 'markers-O', 'near-O', 'the-O', '(CTG)-O', 'n-O', 'repeat-O', 'region-O', 'and-O', 'constructed-O', 'haplotypes.-O']
['Six-O', 'different-O', 'haplotypes-O', 'were-O', 'found-O', 'and-O', 'DM-B-Modifier', 'alleles-O', 'were-O', 'always-O', 'haplotype-O', 'A.-O']
['To-O', 'find-O', 'an-O', 'origin-O', 'of-O', 'the-O', '(CTG)-O', 'n-O', 'repeat-O', 'mutation-O', 'and-O', 'to-O', 'investigate-O', 'the-O', 'mechanism-O', 'of-O', 'the-O', 'expansion-O', 'mutation-O', 'in-O', 'the-O', 'Japanese-O', 'population-O', 'we-O', 'have-O', 'studied-O', '90-O', 'Japanese-O', 'DM-B-SpecificDisease', 'families-O', 'comprising-O', '190-O', 'affected-O', 'and-O', '130-O', 'unaffected-O', 'members.-O']
['The-O', 'results-O', 'suggest-O', 'that-O', 'a-O', 'few-O', 'common-O', 'ancestral-O', 'mutations-O', 'in-O', 'both-O', 'Caucasian-O', 'and-O', 'Japanese-O', 'populations-O', 'have-O', 'originated-O', 'by-O', 'expansion-O', 'of-O', 'an-O', 'ancestral-O', 'n-O', '='-O', '5-O', 'repeat-O', 'to-O', 'n-O', '='-O', '19-37-O', 'copies.-O']
['These-O', 'data-O', 'support-O', 'multistep-O', 'models-O', 'of-O', 'triplet-O', 'repeat-O', 'expansion-O', 'that-O', 'have-O', 'been-O', 'proposed-O', 'for-O', 'both-O', 'DM-B-Modifier', 'and-O', 'Friedreichs-B-SpecificDisease', 'ataxia..-I-SpecificDisease']
['Molecular-O', 'heterogeneity-O', 'in-O', 'mucopolysaccharidosis-B-SpecificDisease', 'IVA-I-SpecificDisease', 'in-O', 'Australia-O', 'and-O', 'Northern-O', 'Ireland:-O', 'nine-O', 'novel-O', 'mutations-O', 'including-O', 'T312S,-O', 'a-O', 'common-O', 'allele-O', 'that-O', 'confers-O', 'a-O', 'mild-O', 'phenotype.-O']
['Mucopolysaccharidosis-B-SpecificDisease', 'IVA-I-SpecificDisease', '(MPS-O', 'IVA)-I-SpecificDisease', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'lysosomal-B-DiseaseClass', 'storage-I-DiseaseClass', 'disorder-I-DiseaseClass', 'caused-O', 'by-O', 'a-O', 'genetic-O', 'defect-O', 'in-O', 'N-acetylgalactosamine-6-sulfate-I-SpecificDisease', 'sulfatase-I-SpecificDisease', '(GALNS).-O', 'Previous-O', 'studies-O', 'of-O', 'patients-O', 'from-O', 'a-O', 'British-Irish-O', 'population-O', 'showed-O', 'that-O', 'the-O', 'I113F-O', 'mutation-O', 'is-O', 'the-O', 'most-O', 'common-O', 'single-O', 'mutation-O', 'among-O', 'MPS-B-SpecificDisease', 'IVA-I-SpecificDisease', 'patients-O', 'and-O', 'produces-O', 'a-O', 'severe-O', 'clinical-O', 'phenotype.-O']
['We-O', 'studied-O', 'mutations-O', 'in-O', 'the-O', 'GALNS-O', 'gene-O', 'from-O', '23-O', 'additional-O', 'MPS-B-Modifier', 'IVA-I-Modifier', 'patients-O', '(15-O', 'from-O', 'Australia,-O', '8-O', 'from-O', 'Northern-O', 'Ireland),-O', 'with-O', 'various-O', 'clinical-O', 'phenotypes-O', '(severe,-O', '16-O', 'cases;-O', 'intermediate,-O', '4-O', 'cases;-O', 'mild,-O', '3-O', 'cases).-O', 'We-O', 'found-O', 'two-O', 'common-O', 'mutations-O', 'that-O', 'together-O', 'accounted-O', 'for-O', '32%-O', 'of-O', 'the-O', '44-O', 'unrelated-O', 'alleles-O', 'in-O', 'these-O', 'patients.-O']
['One-O', 'is-O', 'the-O', 'T312S-O', 'mutation,-O', 'a-O', 'novel-O', 'mutation-O', 'found-O', 'exclusively-O', 'in-O', 'milder-O', 'patients.-O']
['The-O', 'other-O', 'is-O', 'the-O', 'previously-O', 'described-O', 'I113F-O', 'that-O', 'produces-O', 'a-O', 'severe-O', 'phenotype.-B-DiseaseClass']
['The-O', 'I113F-O', 'and-O', 'T312S-O', 'mutations-O', 'accounted-O', 'for-O', '8-O', '(18%)-O', 'and-O', '6-O', '(14%)-O', 'of-O', '44-O', 'unrelated-O', 'alleles,-O', 'respectively.-O']
['The-O', 'relatively-O', 'high-O', 'residual-O', 'GALNS-O', 'activity-O', 'seen-O', 'when-O', 'the-O', 'T312S-O', 'mutant-O', 'cDNA-O', 'is-O', 'overexpressed-O', 'in-O', 'mutant-O', 'cells-O', 'provides-O', 'an-O', 'explanation-O', 'for-O', 'the-O', 'mild-O', 'phenotype-O', 'in-O', 'patients-O', 'with-O', 'this-O', 'mutation.-O']
['The-O', 'distribution-O', 'and-O', 'relative-O', 'frequencies-O', 'of-O', 'the-O', 'I113F-O', 'and-O', 'T312S-O', 'mutations-O', 'in-O', 'Australia-O', 'corresponded-O', 'to-O', 'those-O', 'observed-O', 'in-O', 'Northern-O', 'Ireland-O', 'and-O', 'are-O', 'unique-O', 'to-O', 'these-O', 'two-O', 'populations,-O', 'suggesting-O', 'that-O', 'both-O', 'mutations-O', 'were-O', 'probably-O', 'introduced-O', 'to-O', 'Australia-O', 'by-O', 'Irish-O', 'migrants-O', 'during-O', 'the-O', '19th-O', 'century.-O']
['Haplotype-O', 'analysis-O', 'using-O', '6-O', 'RFLPs-O', 'provides-O', 'additional-O', 'data-O', 'that-O', 'the-O', 'I113F-B-Modifier', 'mutation-O', 'originated-O', 'from-O', 'a-O', 'common-O', 'ancestor.-O']
['The-O', 'other-O', '9-O', 'novel-O', 'mutations-O', 'identified-O', 'in-O', 'these-O', '23-O', 'patients-O', 'were-O', 'each-O', 'limited-O', 'to-O', 'a-O', 'single-O', 'family.-O']
['These-O', 'data-O', 'provide-O', 'further-O', 'evidence-O', 'for-O', 'extensive-O', 'allelic-O', 'heterogeneity-O', 'in-O', 'MPS-B-SpecificDisease', 'IVA-I-SpecificDisease', 'in-O', 'British-Irish-O', 'patients-O', 'and-O', 'provide-O', 'evidence-O', 'for-O', 'their-O', 'transmission-O', 'to-O', 'Australia-O', 'by-O', 'British-Irish-O', 'migrants..-O']
['The-O', 'APCI1307K-O', 'allele-O', 'and-O', 'cancer-B-DiseaseClass', 'risk-O', 'in-O', 'a-O', 'community-based-O', 'study-O', 'of-O', 'Ashkenazi-O', 'Jews.-O']
['Mutations-O', 'in-O', 'APC-B-Modifier', 'are-O', 'classically-O', 'associated-O', 'with-O', 'familial-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-O', '(FAP),-O', 'a-O', 'highly-O', 'penetrant-O', 'autosomal-O', 'dominant-O', 'disorder-O', 'characterized-O', 'by-O', 'multiple-O', 'intestinal-O', 'polyps-O', 'and,-O', 'without-O', 'surgical-O', 'intervention,-O', 'the-O', 'development-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer-O', '(CRC).-I-SpecificDisease', 'APC-O', 'is-O', 'a-O', 'tumour-suppressor-I-Modifier', 'gene,-O', 'and-O', 'somatic-O', 'loss-O', 'occurs-O', 'in-O', 'tumours.-B-DiseaseClass', 'The-O', 'germline-O', 'T-to-A-O', 'transversion-O', 'responsible-O', 'for-O', 'the-O', 'APC-O', 'I1307K-O', 'allele-O', 'converts-O', 'the-O', 'wild-type-O', 'sequence-O', 'to-O', 'a-O', 'homopolymer-O', 'tract-O', '(A8)-O', 'that-O', 'is-O', 'genetically-O', 'unstable-O', 'and-O', 'prone-O', 'to-O', 'somatic-O', 'mutation.-O']
['The-O', 'I1307K-O', 'allele-O', 'was-O', 'found-O', 'in-O', '6.-O']
['1%-O', 'of-O', 'unselected-O', 'Ashkenazi-O', 'Jews-O', 'and-O', 'higher-O', 'proportions-O', 'of-O', 'Ashkenazim-O', 'with-O', 'family-O', 'or-O', 'personal-O', 'histories-O', 'of-O', 'CRC-B-SpecificDisease', '(ref.-O']
['2).-O', 'To-O', 'evaluate-O', 'the-O', 'role-O', 'of-O', 'I1307K-O', 'in-O', 'cancer,-O', 'we-O', 'genotyped-O', '5,-O', '081-O', 'Ashkenazi-O', 'volunteers-O', 'in-O', 'a-O', 'community-O', 'survey.-O']
['Risk-O', 'of-O', 'developing-O', 'colorectal,-B-CompositeMention', 'breast-I-CompositeMention', 'and-O', 'other-O', 'cancers-I-CompositeMention', 'were-O', 'compared-O', 'between-O', 'genotyped-O', 'I1307K-O', 'carriers-O', 'and-O', 'non-carriers-O', 'and-O', 'their-O', 'first-degree-O', 'relatives.-O']
['Low-O', 'frequency-O', 'of-O', 'BRCA1-O', 'germline-O', 'mutations-O', 'in-O', '45-O', 'German-O', 'breast/ovarian-B-Modifier', 'cancer-I-Modifier', 'families.-O']
['In-O', 'this-O', 'study-O', 'we-O', 'investigated-O', '45-O', 'German-O', 'breast/ovarian-B-Modifier', 'cancer-I-Modifier', 'families-O', 'for-O', 'germline-O', 'mutations-O', 'in-O', 'the-O', 'BRCA1-O', 'gene.-O']
['We-O', 'identified-O', 'four-O', 'germline-O', 'mutations-O', 'in-O', 'three-O', 'breast-B-Modifier', 'cancer-I-Modifier', 'families-O', 'and-O', 'in-O', 'one-O', 'breast-ovarian-B-CompositeMention', 'cancer-I-CompositeMention', 'family.-O']
['among-O', 'these-O', 'were-O', 'one-O', 'frameshift-O', 'mutation,-O', 'one-O', 'nonsense-O', 'mutation,-O', 'one-O', 'novel-O', 'splice-O', 'site-O', 'mutation,-O', 'and-O', 'one-O', 'missense-O', 'mutation.-O']
['The-O', 'missense-O', 'mutation-O', 'was-O', 'also-O', 'found-O', 'in-O', '2.-O']
['8%-O', 'of-O', 'the-O', 'general-O', 'population,-O', 'suggesting-O', 'that-O', 'it-O', 'is-O', 'not-O', 'disease-O', 'associated.-O']
['The-O', 'average-O', 'age-O', 'of-O', 'disease-O', 'onset-O', 'in-O', 'those-O', 'families-O', 'harbouring-O', 'causative-O', 'mutations-O', 'was-O', 'between-O', '32.-O']
['3-O', 'and-O', '37-O']
['4-O', 'years,-O', 'whereas-O', 'the-O', 'family-O', 'harbouring-O', 'the-O', 'missense-O', 'mutation-O', 'had-O', 'an-O', 'average-O', 'age-O', 'of-O', 'onset-O', 'of-O', '51.-O']
['2-O', 'years.-O']
['These-O', 'findings-O', 'show-O', 'that-O', 'BRCA1-O', 'is-O', 'implicated-O', 'in-O', 'a-O', 'small-O', 'fraction-O', 'of-O', 'breast/ovarian-B-Modifier', 'cancer-I-Modifier', 'families-O', 'suggesting-O', 'the-O', 'involvement-O', 'of-O', 'another-O', 'susceptibility-O', 'gene,-O', '(s)-O']
['Clustering-O', 'of-O', 'missense-O', 'mutations-O', 'in-O', 'the-O', 'ataxia-telangiectasia-B-SpecificDisease', 'gene-O', 'in-O', 'a-O', 'sporadic-O', 'T-cell-O', 'leukaemia.-O', 'Ataxia-telangiectasia-B-SpecificDisease', '(A-T)-O', 'is-O', 'a-O', 'recessive-B-DiseaseClass', 'multi-system-I-DiseaseClass', 'disorder-I-DiseaseClass', 'caused-O', 'by-O', 'mutations-O', 'in-O', 'the-O', 'ATM-O', 'gene-O', 'at-O', '11q22-q23-O', '(ref.-O']
['3).-O', 'The-O', 'risk-O', 'of-O', 'cancer,-B-DiseaseClass', 'especially-O', 'lymphoid-B-SpecificDisease', 'neoplasias,-I-SpecificDisease', 'is-O', 'substantially-O', 'elevated-O', 'in-O', 'A-T-B-SpecificDisease', 'patients-O', 'and-O', 'has-O', 'long-O', 'been-O', 'associated-O', 'with-O', 'chromosomal-O', 'instability.-O']
['By-O', 'analysing-O', 'tumour-O', 'DNA-O', 'from-O', 'patients-O', 'with-O', 'sporadic-B-SpecificDisease', 'T-cell-I-SpecificDisease', 'prolymphocytic-I-SpecificDisease', 'leukaemia,-I-SpecificDisease', '(T-PLL),-O', 'a-O', 'rare-O', 'clonal-O', 'malignancy-O', 'with-O', 'similarities-O', 'to-O', 'a-O', 'mature-O', 'T-cell-O', 'leukaemia,-O', 'seen-O', 'in-O', 'A-T,-B-SpecificDisease', 'we-O', 'demonstrate-O', 'a-O', 'high-O', 'frequency-O', 'of-O', 'ATM-O', 'mutations-O', 'in-O', 'T-PLL.-O', 'In-O', 'marked-O', 'contrast-O', 'to-O', 'the-O', 'ATM-O', 'mutation-O', 'pattern-O', 'in-O', 'A-T,-O', 'the-O', 'most-O', 'frequent-O', 'nucleotide-O', 'changes-O', 'in-O', 'this-O', 'leukaemia-O', 'were-O', 'missense-O', 'mutations.-O']
['These-O', 'clustered-O', 'in-O', 'the-O', 'region-O', 'corresponding-O', 'to-O', 'the-O', 'kinase-O', 'domain,-O', 'which-O', 'is-O', 'highly-O', 'conserved-O', 'in-O', 'ATM-related-B-Modifier', 'proteins-O', 'in-O', 'mouse,-O', 'yeast-O', 'and-O', 'Drosophila.-O']
['The-O', 'resulting-O', 'amino-acid-O', 'substitutions-O', 'are-O', 'predicted-O', 'to-O', 'interfere-O', 'with-O', 'ATP-O', 'binding-O', 'or-O', 'substrate-O', 'recognition.-O']
['Two-O', 'of-O', 'seventeen-O', 'mutated-O', 'T-PLL-B-Modifier', 'samples-O', 'had-O', 'a-O', 'previously-O', 'reported-O', 'A-T-O', 'allele.-O']
['In-O', 'contrast,-O', 'no-O', 'mutations-O', 'were-O', 'detected-O', 'in-O', 'the-O', 'p53-O', 'gene,-O', 'suggesting-O', 'that-O', 'this-O', 'tumour-B-Modifier', 'suppressor-O', 'is-O', 'not-O', 'frequently-O', 'altered-O', 'in-O', 'this-O', 'leukaemia.-O', 'Occasional-O', 'missense-O', 'mutations-O', 'in-O', 'ATM-O', 'were-O', 'also-O', 'found-O', 'in-O', 'tumour-B-Modifier', 'DNA-O', 'from-O', 'patients-O', 'with-O', 'B-cell-B-SpecificDisease', 'non-Hodgkins-O', 'lymphomas,-I-SpecificDisease', '(B-NHL)-I-SpecificDisease', 'and-O', 'a-O', 'B-NHL-I-SpecificDisease', 'cell-O', 'line.-O']
['The-O', 'evidence-O', 'of-O', 'a-O', 'significant-O', 'proportion-O', 'of-O', 'loss-of-function-O', 'mutations-O', 'and-O', 'a-O', 'complete-O', 'absence-O', 'of-O', 'the-O', 'normal-O', 'copy-O', 'of-O', 'ATM-O', 'in-O', 'the-O', 'majority-O', 'of-O', 'mutated-O', 'tumours-B-DiseaseClass', 'establishes-O', 'somatic-O', 'inactivation-O', 'of-O', 'this-O', 'gene-O', 'in-O', 'the-O', 'pathogenesis-O', 'of-O', 'sporadic-B-SpecificDisease', 'T-PLL-B-SpecificDisease', 'and-O', 'suggests-O', 'that-O', 'ATM-O', 'acts-O', 'as-O', 'a-O', 'tumour-B-Modifier', 'suppressor-O', '.-O']
['As-O', 'constitutional-O', 'DNA-O', 'was-O', 'not-O', 'available,-O', 'a-O', 'putative-O', 'hereditary-B-DiseaseClass', 'predisposition-O', 'to-O', 'T-PLL-B-SpecificDisease', 'will-O', 'require-O', 'further-O', 'investigation..-O']
['A-O', 'mouse-O', 'model-O', 'of-O', 'severe-B-SpecificDisease', 'von-I-SpecificDisease', 'Willebrand-I-SpecificDisease', 'disease:-I-SpecificDisease', 'defects-O', 'in-O', 'hemostasis-O', 'and-O', 'thrombosis.-O', 'von-B-Modifier', 'Willebrand-I-Modifier', 'factor-O', '(vWf)-O', 'deficiency-O', 'causes-O', 'severe-B-SpecificDisease', 'von-I-SpecificDisease', 'Willebrand-I-SpecificDisease', 'disease-O', 'in-O', 'humans.-O']
['We-O', 'generated-O', 'a-O', 'mouse-O', 'model-O', 'for-O', 'this-O', 'disease-I-DiseaseClass', 'by-O', 'using-O', 'gene-O', 'targeting.-O']
['vWf-deficient-B-Modifier', 'mice-O', 'appeared-O', 'normal-O', 'at-O', 'birth;-O', 'they-O', 'were-O', 'viable-O', 'and-O', 'fertile.-O']
['Neither-O', 'vWf-O', 'nor-O', 'vWf-O', 'propolypeptide-O', '(von-B-Modifier', 'Willebrand-I-Modifier', 'antigen-O', 'II)-O', 'were-O', 'detectable-O', 'in-O', 'plasma,-O', 'platelets,-O', 'or-O', 'endothelial-O', 'cells-O', 'of-O', 'the-O', 'homozygous-O', 'mutant-O', 'mice.-O']
['The-O', 'mutant-O', 'mice-O', 'exhibited-O', 'defects-O', 'in-O', 'hemostasis-O', 'with-O', 'a-O', 'highly-O', 'prolonged-O', 'bleeding-O', 'time-O', 'and-O', 'spontaneous-O', 'bleeding-O', 'events-O', 'in-O', 'approximately-O', '10%-O', 'of-O', 'neonates.-O']
['As-O', 'in-O', 'the-O', 'human-O', 'disease,-O', 'the-O', 'factor-O', 'VIII-O', 'level-O', 'in-O', 'these-O', 'mice-O', 'was-O', 'reduced-O', 'strongly-O', 'as-O', 'a-O', 'result-O', 'of-O', 'the-O', 'lack-O', 'of-O', 'protection-O', 'provided-O', 'by-O', 'vWf.-O']
['Defective-O', 'thrombosis-B-DiseaseClass', 'in-O', 'mutant-O', 'mice-O', 'was-O', 'also-O', 'evident-O', 'in-O', 'an-O', 'in-O', 'vivo-O', 'model-O', 'of-O', 'vascular-B-DiseaseClass', 'injury.-I-DiseaseClass', 'In-O', 'this-O', 'model,-O', 'the-O', 'exteriorized-O', 'mesentery-O', 'was-O', 'superfused-O', 'with-O', 'ferric-O', 'chloride-O', 'and-O', 'the-O', 'accumulation-O', 'of-O', 'fluorescently-O', 'labeled-O', 'platelets-O', 'was-O', 'observed-O', 'by-O', 'intravital-O', 'microscopy.-O']
['We-O', 'conclude-O', 'that-O', 'these-O', 'mice-O', 'very-O', 'closely-O', 'mimic-O', 'severe-B-SpecificDisease', 'human-O', 'von-B-SpecificDisease', 'Willebrand-I-SpecificDisease', 'disease-I-SpecificDisease', 'and-O', 'will-O', 'be-O', 'very-O', 'useful-O', 'for-O', 'investigating-O', 'the-O', 'role-O', 'of-O', 'vWf-O', 'in-O', 'normal-O', 'physiology-O', 'and-O', 'in-O', 'disease-O', 'models..-O']
['Somatic-O', 'instability-O', 'of-O', 'the-O', 'CTG-O', 'repeat-O', 'in-O', 'mice-O', 'transgenic-O', 'for-O', 'the-O', 'myotonic-B-Modifier', 'dystrophy-I-Modifier', 'region-O', 'is-O', 'age-O', 'dependent-O', 'but-O', 'not-O', 'correlated-O', 'to-O', 'the-O', 'relative-O', 'intertissue-O', 'transcription-O', 'levels-O', 'and-O', 'proliferative-O', 'capacities.-O']
['A-O', '(CTG)-O', 'nexpansion-O', 'in-O', 'the-O', '3-untranslated-O', 'region-O', '(UTR)-O', 'of-O', 'the-O', 'DM-B-Modifier', 'protein-O', 'kinase-O', 'gene-O', '(DMPK)-O', 'is-O', 'responsible-O', 'for-O', 'causing-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', '(DM).-O', 'Major-O', 'instability,-O', 'with-O', 'very-O', 'large-O', 'expansions-O', 'between-O', 'generations-O', 'and-O', 'high-O', 'levels-O', 'of-O', 'somatic-O', 'mosaicism,-O', 'is-O', 'observed-O', 'in-O', 'patients.-O']
['There-O', 'is-O', 'a-O', 'good-O', 'correlation-O', 'between-O', 'repeat-O', 'size-O', '(at-O', 'least-O', 'in-O', 'leucocytes),-O', 'clinical-O', 'severity-O', 'and-O', 'age-O', 'of-O', 'onset.-O']
['The-O', 'trinucleotide-O', 'repeat-O', 'instability-O', 'mechanisms-O', 'involved-O', 'in-O', 'DM-B-Modifier', 'and-O', 'other-O', 'human-O', 'genetic-O', 'diseases-I-DiseaseClass', 'are-O', 'unknown.-O']
['We-O', 'studied-O', 'somatic-O', 'instability-O', 'by-O', 'measuring-O', 'the-O', 'CTG-O', 'repeat-O', 'length-O', 'at-O', 'several-O', 'ages-O', 'in-O', 'various-O', 'tissues-O', 'of-O', 'transgenic-O', 'mice-O', 'carrying-O', 'a-O', '(CTG)-O', '55expansion-O', 'surrounded-O', 'by-O', '45-O', 'kb-O', 'of-O', 'the-O', 'human-O', 'DM-B-Modifier', 'region,-O', 'using-O', 'small-pool-O', 'PCR.-O']
['These-O', 'mice-O', 'have-O', 'been-O', 'shown-O', 'to-O', 'reproduce-O', 'the-O', 'intergenerational-O', 'and-O', 'somatic-O', 'instability-O', 'of-O', 'the-O', '55-O', 'CTG-O', 'repeat-O', 'suggesting-O', 'that-O', 'surrounding-O', 'sequences-O', 'and-O', 'the-O', 'chromatin-O', 'environment-O', 'are-O', 'involved-O', 'in-O', 'instability-O', 'mechanisms.-O']
['As-O', 'observed-O', 'in-O', 'some-O', 'of-O', 'the-O', 'tissues-O', 'of-O', 'DM-B-Modifier', 'patients,-O', 'there-O', 'is-O', 'a-O', 'tendency-O', 'for-O', 'repeat-O', 'length-O', 'and-O', 'somatic-O', 'mosaicism-O', 'to-O', 'increase-O', 'with-O', 'the-O', 'age-O', 'of-O', 'the-O', 'mouse.-O']
['Furthermore,-O', 'we-O', 'observed-O', 'no-O', 'correlation-O', 'between-O', 'the-O', 'somatic-O', 'mutation-O', 'rate-O', 'and-O', 'tissue-O', 'proliferation-O', 'capacity.-O']
['The-O', 'somatic-O', 'mutation-O', 'rates-O', 'in-O', 'different-O', 'tissues-O', 'were-O', 'also-O', 'not-O', 'correlated-O', 'to-O', 'the-O', 'relative-O', 'inter-tissue-O', 'difference-O', 'in-O', 'transcriptional-O', 'levels-O', 'of-O', 'the-O', 'three-O', 'genes-O', '(DMAHP,-O', 'DMPK-O', 'and-O', '59)-O', 'surrounding-O', 'the-O', 'repeat..-O']
['The-O', 'molecular-O', 'basis-O', 'of-O', 'C6-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'in-O', 'the-O', 'western-O', 'Cape,-O', 'South-O', 'Africa.-O']
['Deficiency-B-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'sixth-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'human-I-SpecificDisease', 'complement-I-SpecificDisease', '(C6)-O', 'has-O', 'been-O', 'reported-O', 'in-O', 'a-O', 'number-O', 'of-O', 'families-O', 'from-O', 'the-O', 'western-O', 'Cape,-O', 'South-O', 'Africa.-O']
['Meningococcal-B-SpecificDisease', 'disease-I-SpecificDisease', 'is-O', 'endemic-O', 'in-O', 'the-O', 'Cape-O', 'and-O', 'almost-O', 'all-O', 'pedigrees-O', 'of-O', 'total-O', 'C6-B-SpecificDisease', 'deficiency-(C6Q0)-I-SpecificDisease', 'have-O', 'been-O', 'ascertained-O', 'because-O', 'of-O', 'recurrent-O', 'disease.-I-SpecificDisease']
['We-O', 'have-O', 'sequenced-O', 'the-O', 'expressed-O', 'exons-O', 'of-O', 'the-O', 'C6-B-SpecificDisease', 'gene-O', 'from-O', 'selected-O', 'cases-O', 'and-O', 'have-O', 'found-O', 'three-O', 'molecular-O', 'defects-O', 'leading-O', 'to-O', 'total-O', 'deficiency-O', '879delG,-I-SpecificDisease', 'which-O', 'is-O', 'the-O', 'common-O', 'defect-O', 'in-O', 'the-O', 'Cape-O', 'and-O', 'hitherto-O', 'unreported,-O', 'and-O', '1195delC-O', 'and-O', '1936delG,-O', 'which-O', 'have-O', 'been-O', 'previously-O', 'reported-O', 'in-O', 'African-Americans.-O']
['We-O', 'also-O', 'show-O', 'that-O', 'the-O', '879delG-O', 'and-O', '1195delC-O', 'defects-O', 'are-O', 'associated-O', 'with-O', 'characteristic-O', 'C6/C7-B-Modifier', 'region-O', 'DNA-O', 'marker-O', 'haplotypes,-O', 'although-O', 'small-O', 'variations-O', 'were-O', 'observed.-O']
['The-O', '1936delG-O', 'defect-O', 'was-O', 'observed-O', 'only-O', 'once-O', 'in-O', 'the-O', 'Cape,-O', 'but-O', 'its-O', 'associated-O', 'haplotype-O', 'could-O', 'be-O', 'deduced.-O']
['The-O', 'data-O', 'from-O', 'the-O', 'haplotypes-O', 'indicate-O', 'that-O', 'these-O', 'three-O', 'molecular-O', 'defects-O', 'account-O', 'for-O', 'the-O', 'defects-O', 'in-O', 'all-O', 'the-O', '38-O', 'unrelated-O', 'C6Q0-O', 'individuals-O', 'we-O', 'have-O', 'studied-O', 'from-O', 'the-O', 'Cape.-O']
['We-O', 'have-O', 'also-O', 'observed-O', 'the-O', '879delG-O', 'defect-O', 'in-O', 'two-O', 'Dutch-O', 'C6-deficient-B-SpecificDisease', 'kindreds,-O', 'but-O', 'the-O', '879delG-O', 'defect-O', 'in-O', 'the-O', 'Cape-O', 'probably-O', 'did-O', 'not-O', 'come-O', 'from-O', 'The-O', 'Netherlands..-O']
['A-O', 'mouse-O', 'model-O', 'for-O', 'Prader-Willi-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'imprinting-centre-O', 'mutations.-O']
['Imprinting-O', 'in-O', 'the-O', '15q11-q13-O', 'region-O', 'involves-O', 'an-O', 'imprinting-O', 'centre-O', '(IC),-O', 'mapping-O', 'in-O', 'part-O', 'to-O', 'the-O', 'promoter-O', 'and-O', 'first-O', 'exon-O', 'of-O', 'SNRPN.-O']
['Deletion-O', 'of-O', 'this-O', 'IC-O', 'abolishes-O', 'local-O', 'paternally-O', 'derived-O', 'gene-O', 'expression-O', 'and-O', 'results-O', 'in-O', 'Prader-Willi-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(PWS).-O', 'We-O', 'have-O', 'created-O', 'two-O', 'deletion-O', 'mutations-O', 'in-O', 'mice-O', 'to-O', 'understand-O', 'PWS-B-Modifier', 'and-O', 'the-O', 'mechanism-O', 'of-O', 'this-O', 'IC.-O']
['Mice-O', 'harbouring-O', 'an-O', 'intragenic-O', 'deletion-O', 'in-O', 'Snrpn-O', 'are-O', 'phenotypically-O', 'normal,-O', 'suggesting-O', 'that-O', 'mutations-O', 'of-O', 'SNRPN-O', 'are-O', 'not-O', 'sufficient-O', 'to-O', 'induce-O', 'PWS.-B-SpecificDisease', 'Mice-O', 'with-O', 'a-O', 'larger-O', 'deletion-O', 'involving-O', 'both-O', 'Snrpn-O', 'and-O', 'the-O', 'putative-O', 'PWS-IC-O', 'lack-O', 'expression-O', 'of-O', 'the-O', 'imprinted-O', 'genes-O', 'Zfp127-O', '(mouse-O', 'homologue-O', 'of-O', 'ZNF127),-O', 'Ndn-O', 'and-O', 'Ipw,-O', 'and-O', 'manifest-O', 'several-O', 'phenotypes-O', 'common-O', 'to-O', 'PWS-B-SpecificDisease', 'infants.-O']
['These-O', 'data-O', 'demonstrate-O', 'that-O', 'both-O', 'the-O', 'position-O', 'of-O', 'the-O', 'IC-O', 'and-O', 'its-O', 'role-O', 'in-O', 'the-O', 'coordinate-O', 'expression-O', 'of-O', 'genes-O', 'is-O', 'conserved-O', 'between-O', 'mouse-O', 'and-O', 'human,-O', 'and-O', 'indicate-O', 'that-O', 'the-O', 'mouse-O', 'is-O', 'a-O', 'suitable-O', 'model-O', 'system-O', 'in-O', 'which-O', 'to-O', 'investigate-O', 'the-O', 'molecular-O', 'mechanisms-O', 'of-O', 'imprinting-O', 'in-O', 'this-O', 'region-O', 'of-O', 'the-O', 'genome..-O']
['Distribution-O', 'of-O', 'emerin-O', 'and-O', 'lamins-O', 'in-O', 'the-O', 'heart-O', 'and-O', 'implications-O', 'for-O', 'Emery-Dreifuss-B-SpecificDisease', 'muscular-I-SpecificDisease', 'dystrophy-I-SpecificDisease.', 'Emerin-O', 'is-O', 'a-O', 'nuclear-O', 'membrane-O', 'protein-O', 'which-O', 'is-O', 'missing-O', 'or-O', 'defective-O', 'in-O', 'Emery-Dreifuss-B-SpecificDisease', 'muscular-I-SpecificDisease', 'dystrophy-I-SpecificDisease', '(EDMD).-O', 'It-O', 'is-O', 'one-O', 'member-O', 'of-O', 'a-O', 'family-O', 'of-O', 'lamina-associated-O', 'proteins-O', 'which-O', 'includes-O', 'LAP1,-O', 'LAP2-O', 'and-O', 'lamin-O', 'B-O', 'receptor-O', '(LBR).-O', 'A-O', 'panel-O', 'of-O', '16-O', 'monoclonal-O', 'antibodies-O', '(mAbs)-O', 'has-O', 'been-O', 'mapped-O', 'to-O', 'six-O', 'specific-O', 'sites-O', 'throughout-O', 'the-O', 'emerin-O', 'molecule-O', 'using-O', 'phage-displayed-O', 'peptide-O', 'libraries-O', 'and-O', 'has-O', 'been-O', 'used-O', 'to-O', 'localize-O', 'emerin-O', 'in-O', 'human-O', 'and-O', 'rabbit-O', 'heart.-O']
['Several-O', 'mAbs-O', 'against-O', 'different-O', 'emerin-O', 'epitopes-O', 'did-O', 'not-O', 'recognize-O', 'intercalated-O', 'discs-O', 'in-O', 'the-O', 'heart,-O', 'though-O', 'they-O', 'recognized-O', 'cardiomyocyte-O', 'nuclei-O', 'strongly,-O', 'both-O', 'at-O', 'the-O', 'rim-O', 'and-O', 'in-O', 'intranuclear-O', 'spots-O', 'or-O', 'channels.-O']
['A-O', 'polyclonal-O', 'rabbit-O', 'antiserum-O', 'against-O', 'emerin-O', 'did-O', 'recognize-O', 'both-O', 'nuclear-O', 'membrane-O', 'and-O', 'intercalated-O', 'discs-O', 'but,-O', 'after-O', 'affinity-O', 'purification-O', 'against-O', 'a-O', 'pure-emerin-O', 'band-O', 'on-O', 'a-O', 'western-O', 'blot,-O', 'it-O', 'stained-O', 'only-O', 'the-O', 'nuclear-O', 'membrane.-O']
['These-O', 'results-O', 'would-O', 'not-O', 'be-O', 'expected-O', 'if-O', 'immunostaining-O', 'at-O', 'intercalated-O', 'discs-O', 'were-O', 'due-O', 'to-O', 'a-O', 'product-O', 'of-O', 'the-O', 'emerin-O', 'gene-O', 'and,-O', 'therefore,-O', 'cast-O', 'some-O', 'doubt-O', 'upon-O', 'the-O', 'hypothesis-O', 'that-O', 'cardiac-B-SpecificDisease', 'defects-O', 'in-O', 'EDMD-B-Modifier', 'are-O', 'caused-O', 'by-O', 'absence-O', 'of-O', 'emerin-O', 'from-O', 'intercalated-O', 'discs.-O']
['Although-O', 'emerin-O', 'was-O', 'abundant-O', 'in-O', 'the-O', 'membranes-O', 'of-O', 'cardiomyocyte-O', 'nuclei,-O', 'it-O', 'was-O', 'absent-O', 'from-O', 'many-O', 'non-myocyte-O', 'cells-O', 'in-O', 'the-O', 'heart.-O']
['This-O', 'distribution-O', 'of-O', 'emerin-O', 'was-O', 'similar-O', 'to-O', 'that-O', 'of-O', 'lamin-O', 'A,-O', 'a-O', 'candidate-O', 'gene-O', 'for-O', 'an-O', 'autosomal-O', 'form-O', 'of-O', 'EDMD-B-SpecificDisease', '.', 'In-O', 'contrast,-O', 'lamin-O', 'B1-O', 'was-O', 'absent-O', 'from-O', 'cardiomyocyte-O', 'nuclei,-O', 'showing-O', 'that-O', 'lamin-O', 'B1-O', 'is-O', 'not-O', 'essential-O', 'for-O', 'localization-O', 'of-O', 'emerin-O', 'to-O', 'the-O', 'nuclear-O', 'lamina.-O']
['Lamin-O', 'B1-O', 'is-O', 'also-O', 'almost-O', 'completely-O', 'absent-O', 'from-O', 'skeletal-O', 'muscle-O', 'nuclei.-O']
['In-O', 'EDMD,-B-SpecificDisease', 'the-O', 'additional-O', 'absence-O', 'of-O', 'lamin-O', 'B1-O', 'from-O', 'heart-O', 'and-O', 'skeletal-O', 'muscle-O', 'nuclei-O', 'which-O', 'already-O', 'lack-O', 'emerin-O', 'may-O', 'offer-O', 'an-O', 'alternative-O', 'explanation-O', 'of-O', 'why-O', 'these-O', 'tissues-O', 'are-O', 'particularly-O', 'affected..-O']
['Prevalence-O', 'of-O', 'p16-O', 'and-O', 'CDK4-O', 'germline-O', 'mutations-O', 'in-O', '48-O', 'melanoma-prone-O', 'families-O', 'in-O', 'France.-O']
['The-O', 'French-O', 'Familial-B-Modifier', 'Melanoma-B-SpecificDisease', 'Study-O', 'Group.-O']
['Germline-O', 'mutations-O', 'in-O', 'the-O', 'p16-O', 'and-O', 'CDK4-O', 'genes-O', 'have-O', 'been-O', 'reported-O', 'in-O', 'a-O', 'subset-O', 'of-O', 'melanoma-B-SpecificDisease', 'pedigrees,-O', 'but-O', 'their-O', 'prevalence-O', 'is-O', 'not-O', 'well-O', 'known.-O']
['We-O', 'searched-O', 'for-O', 'such-O', 'germline-O', 'mutations-O', 'in-O', '48-O', 'French-O', 'melanoma-prone-B-Modifier', 'families-O', 'selected-O', 'according-O', 'to-O', 'two-O', 'major-O', 'criteria-O', 'families-O', 'with-O', 'at-O', 'least-O', 'three-O', 'affected-O', 'members-O', '(n-O', '=', '20)-O', 'or-O', 'families-O', 'with-O', 'two-O', 'affected-O', 'members,-O', 'one-O', 'of-O', 'them-O', 'affected-O', 'before-O', 'the-O', 'age-O', 'of-O', '50-O', '(n-O', '=', '28),-O', 'and-O', 'one-O', 'additional-O', 'minor-O', 'criterion.-O']
['Sixteen-O', 'different-O', 'p16-O', 'germline-O', 'mutations-O', 'were-O', 'found-O', 'in-O', '21-O', 'families,-O', 'while-O', 'one-O', 'germline-O', 'mutation,-O', 'Arg24His,-O', 'was-O', 'detected-O', 'in-O', 'the-O', 'CDK4-O', 'gene.-O']
['The-O', 'frequency-O', 'of-O', 'p16-B-Modifier', 'gene-O', 'mutation-O', 'in-O', 'our-O', 'sample-O', '(44%)-O', 'is-O', 'among-O', 'the-O', 'highest-O', 'rates-O', 'yet-O', 'reported-O', 'and-O', 'the-O', 'CDK4-B-Modifier', 'mutation-O', 'is-O', 'the-O', 'second-O', 'mutation-O', 'detected-O', 'in-O', 'this-O', 'gene-O', 'worldwide.-O']
['In-O', 'summary,-O', 'our-O', 'results-O', 'show-O', 'frequent-O', 'involvement-O', 'of-O', 'the-O', 'p16-B-Modifier', 'gene-O', 'in-O', 'familial-B-SpecificDisease', 'melanoma-I-SpecificDisease', 'and-O', 'confirm-O', 'the-O', 'role-O', 'of-O', 'the-O', 'CDK4-B-Modifier', 'gene-O', 'as-O', 'a-O', 'melanoma-predisposing-O', 'gene..-O']
['A-O', 'novel-O', 'common-O', 'missense-O', 'mutation-O', 'G301C-O', 'in-O', 'the-O', 'N-acetylgalactosamine-6-sulfate-O', 'sulfatase-O', 'gene-O', 'in-O', 'mucopolysaccharidosis-B-SpecificDisease', 'IVA-I-SpecificDisease', '(MPS-O', 'IVA)-I-SpecificDisease', 'is-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'lysosomal-I-DiseaseClass', 'storage-I-DiseaseClass', 'disorder-I-DiseaseClass', 'caused-O', 'by-O', 'a-O', 'genetic-I-DiseaseClass', 'defect-O', 'in-O', 'N-acetylgalactosamine-6-sulfate-O', 'sulfatase-O', '(GALNS).-O', 'In-O', 'previous-O', 'studies,-O', 'we-O', 'have-O', 'found-O', 'two-O', 'common-O', 'mutations-O', 'in-O', 'Caucasians-O', 'and-O', 'Japanese,-O', 'respectively.-O']
['To-O', 'characterize-O', 'the-O', 'mutational-O', 'spectrum-O', 'in-O', 'various-O', 'ethnic-O', 'groups,-O', 'mutations-O', 'in-O', 'the-O', 'GALNS-O', 'gene-O', 'in-O', 'Colombian-O', 'MPS-B-SpecificDisease', 'IVA-I-SpecificDisease', 'patients-O', 'were-O', 'investigated,-O', 'and-O', 'genetic-O', 'backgrounds-O', 'were-O', 'extensively-O', 'analyzed-O', 'to-O', 'identify-O', 'racial-O', 'origin,-O', 'based-O', 'on-O', 'mitochondrial-O', 'DNA-O', '(mtDNA)-O', 'lineages.-O']
['Three-O', 'novel-O', 'missense-O', 'mutations-O', 'never-O', 'identified-O', 'previously-O', 'in-O', 'other-O', 'populations-O', 'and-O', 'found-O', 'in-O', '16-O', 'out-O', 'of-O', '19-O', 'Colombian-O', 'MPS-B-SpecificDisease', 'IVA-I-SpecificDisease', 'unrelated-O', 'alleles-O', 'account-O', 'for-O', '84.-O']
['2%-O', 'of-O', 'the-O', 'alleles-O', 'in-O', 'this-O', 'study.-O']
['The-O', 'G301C-O', 'and-O', 'S162F-O', 'mutations-O', 'account-O', 'for-O', '68.-O']
['4%-O', 'and-O', '10-O']
['5%-O', 'of-O', 'mutations,-O', 'respectively,-O', 'whereas-O', 'the-O', 'remaining-O', 'F69V-O', 'is-O', 'limited-O', 'to-O', 'a-O', 'single-O', 'allele.-O']
['The-O', 'skewed-O', 'prevalence-O', 'of-O', 'G301C-O', 'in-O', 'only-O', 'Colombian-O', 'patients-O', 'and-O', 'haplotype-O', 'analysis-O', 'by-O', 'restriction-O', 'fragment-O', 'length-O', 'polymorphisms-O', 'in-O', 'the-O', 'GALNS-O', 'gene-O', 'suggest-O', 'that-O', 'G301C-O', 'originated-O', 'from-O', 'a-O', 'common-O', 'ancestor.-O']
['Investigation-O', 'of-O', 'the-O', 'genetic-O', 'background-O', 'by-O', 'means-O', 'of-O', 'mtDNA-O', 'lineages-O', 'indicate-O', 'that-O', 'all-O', 'our-O', 'patients-O', 'are-O', 'probably-O', 'of-O', 'native-O', 'American-O', 'descent-O']
['Determination-O', 'of-O', 'the-O', 'genomic-O', 'structure-O', 'of-O', 'the-O', 'COL4A4-B-Modifier', 'gene-O', 'and-O', 'of-O', 'novel-O', 'mutations-O', 'causing-O', 'autosomal-O', 'recessive-O', 'Alport-B-SpecificDisease', 'syndrome.-I-SpecificDisease', 'Autosomal-O', 'recessive-O', 'Alport-B-SpecificDisease', 'syndrome-O', 'is-O', 'a-O', 'progressive-O', 'hematuric-O', 'glomerulonephritis-O', 'characterized-O', 'by-O', 'glomerular-O', 'basement-O', 'membrane-O', 'abnormalities-O', 'and-O', 'associated-O', 'with-O', 'mutations-O', 'in-O', 'either-O', 'the-O', 'COL4A3-B-Modifier', 'or-O', 'the-O', 'COL4A4-B-Modifier', 'gene,-O', 'which-O', 'encode-O', 'the-O', 'alpha3-O', 'and-O', 'alpha4-O', 'type-O', 'IV-O', 'collagen-O', 'chains,-O', 'respectively.-O']
['To-O', 'date,-O', 'mutation-O', 'screening-O', 'in-O', 'the-O', 'two-O', 'genes-O', 'has-O', 'been-O', 'hampered-O', 'by-O', 'the-O', 'lack-O', 'of-O', 'genomic-O', 'structure-O', 'information.-O']
['We-O', 'report-O', 'here-O', 'the-O', 'complete-O', 'characterization-O', 'of-O', 'the-O', '48-O', 'exons-O', 'of-O', 'the-O', 'COL4A4-O', 'gene,-O', 'a-O', 'comprehensive-O', 'gene-O', 'screen,-O', 'and-O', 'the-O', 'subsequent-O', 'detection-O', 'of-O', '10-O', 'novel-O', 'mutations-O', 'in-O', 'eight-O', 'patients-O', 'diagnosed-O', 'with-O', 'autosomal-O', 'recessive-O', 'Alport-B-SpecificDisease', 'syndrome.-O', 'Furthermore,-O', 'we-O', 'identified-O', 'a-O', 'glycine-O', 'to-O', 'alanine-O', 'substitution-O', 'in-O', 'the-O', 'collagenous-O', 'domain-O', 'that-O', 'is-O', 'apparently-O', 'silent-O', 'in-O', 'the-O', 'heterozygous-O', 'carriers,-O', 'in-O', '11.-O']
['5%-O', 'of-O', 'all-O', 'control-O', 'individuals,-O', 'and-O', 'in-O', 'one-O', 'control-O', 'individual-O', 'homozygous-O', 'for-O', 'this-O', 'glycine-O', 'substitution.-O']
['There-O', 'has-O', 'been-O', 'no-O', 'previous-O', 'finding-O', 'of-O', 'a-O', 'glycine-O', 'substitution-O', 'that-O', 'is-O', 'not-O', 'associated-O', 'with-O', 'any-O', 'obvious-O', 'phenotype-O', 'in-O', 'homozygous-O', 'individuals.-O']
['Nonsense-O', 'mutation-O', 'in-O', 'exon-O', '4-O', 'of-O', 'human-O', 'complement-O', 'C9-B-SpecificDisease', 'gene-O', 'is-O', 'the-O', 'major-O', 'cause-O', 'of-O', 'Japanese-O', 'complement-O', 'C9-B-SpecificDisease', 'deficiency.-I-SpecificDisease', 'Deficiency-B-SpecificDisease', 'of-I-SpecificDisease', 'the-I-SpecificDisease', 'ninth-I-SpecificDisease', 'component-I-SpecificDisease', 'of-I-SpecificDisease', 'human-O', 'complement-I-SpecificDisease', '(C9)-O', 'is-O', 'the-O', 'most-O', 'common-O', 'complement-O', 'deficiency-I-SpecificDisease', 'in-O', 'Japan-O', 'but-O', 'is-O', 'rare-O', 'in-O', 'other-O', 'countries.-O']
['We-O', 'studied-O', 'the-O', 'molecular-B-DiseaseClass', 'basis-O', 'of-O', 'C9-B-SpecificDisease', 'deficiency-I-SpecificDisease', 'in-O', 'four-O', 'Japanese-O', 'C9-deficient-B-SpecificDisease', 'patients-O', 'who-O', 'had-O', 'suffered-O', 'from-O', 'meningococcal-B-SpecificDisease', 'meningitis.-I-SpecificDisease', 'Direct-O', 'sequencing-O', 'of-O', 'amplified-O', 'C9-O', 'cDNA-O', 'and-O', 'DNA-O', 'revealed-O', 'a-O', 'nonsense-O', 'substitution-O', '(CGA--', '>', 'TGA)-O', 'at-O', 'codon-O', '95-O', 'in-O', 'exon-O', '4-O', 'in-O', 'the-O', 'four-O', 'C9-deficient-B-SpecificDisease', 'individuals.-O']
['An-O', 'allele-specific-O', 'polymerase-O', 'chain-O', 'reaction-O', 'system-O', 'designed-O', 'to-O', 'detect-O', 'exclusively-O', 'only-O', 'one-O', 'of-O', 'the-O', 'normal-O', 'and-O', 'mutant-O', 'alleles-O', 'indicated-O', 'that-O', 'all-O', 'the-O', 'four-O', 'patients-O', 'were-O', 'homozygous-O', 'for-O', 'the-O', 'mutation-O', 'in-O', 'exon-O', '4-O', 'and-O', 'that-O', 'the-O', 'parents-O', 'of-O', 'patient-O', '2-O', 'were-O', 'heterozygous.-O']
['The-O', 'common-O', 'mutation-O', 'at-O', 'codon-O', '95-O', 'in-O', 'exon-O', '4-O', 'might-O', 'be-O', 'responsible-O', 'for-O', 'most-O', 'Japanese-O', 'C9-B-SpecificDisease', 'deficiency..-I-SpecificDisease']
['Human-O', 'MLH1-O', 'deficiency-I-SpecificDisease', 'predisposes-O', 'to-O', 'hematological-B-DiseaseClass', 'malignancy-I-DiseaseClass', 'and-O', 'neurofibromatosis-B-SpecificDisease', 'type-I-SpecificDisease', '1.-I-SpecificDisease', 'Heterozygous-O', 'germ-line-O', 'mutations-O', 'in-O', 'the-O', 'DNA-O', 'mismatch-O', 'repair-O', 'genes-O', 'lead-O', 'to-O', 'hereditary-B-SpecificDisease', 'nonpolyposis-I-SpecificDisease', 'colorectal-I-SpecificDisease', 'cancer.-I-SpecificDisease', 'The-O', 'disease-O', 'susceptibility-O', 'of-O', 'individuals-O', 'who-O', 'constitutionally-O', 'lack-O', 'both-O', 'wild-type-O', 'alleles-O', 'is-O', 'unknown.-O']
['We-O', 'have-O', 'identified-O', 'three-O', 'offspring-O', 'in-O', 'a-O', 'hereditary-O', 'nonpolyposis-O', 'colorectal-O', 'cancer-B-SpecificDisease', 'family-O', 'who-O', 'developed-O', 'hematological-O', 'malignancy-O', 'at-O', 'a-O', 'very-O', 'early-O', 'age,-O', 'and-O', 'at-O', 'least-O', 'two-O', 'of-O', 'them-O', 'displayed-O', 'signs-O', 'of-O', 'neurofibromatosis-O', 'type-O', '1-O', '(NF1).-B-SpecificDisease', 'DNA-O', 'sequence-O', 'analysis-O', 'and-O', 'allele-specific-O', 'amplification-O', 'in-O', 'two-O', 'siblings-O', 'revealed-O', 'a-O', 'homozygous-O', 'MLH1-O', 'mutation-O', '(C676T--O', '>O', 'Arg226Stop).-O', 'Thus,-O', 'a-O', 'homozygous-O', 'germ-line-O', 'MLH1-O', 'mutation-O', 'and-O', 'consequent-O', 'mismatch-O', 'repair-O', 'deficiency-O', 'results-O', 'in-O', 'a-O', 'mutator-O', 'phenotype-O', 'characterized-O', 'by-O', 'leukemia-B-DiseaseClass', 'and/or-I-DiseaseClass', 'lymphoma-I-DiseaseClass', 'associated-O', 'with-O', 'neurofibromatosis-O', 'type-O', '1..-O']
['The-O', 'DMPK-O', 'gene-O', 'of-O', 'severely-O', 'affected-O', 'myotonic-B-SpecificDisease', 'dystrophy-I-SpecificDisease', 'patients-O', 'is-O', 'hypermethylated-O', 'proximal-O', 'to-O', 'the-O', 'largely-O', 'expanded-O', 'CTG-O', 'repeat.-O']
['Using-O', 'methylation-sensitive-O', 'restriction-O', 'enzymes,-O', 'we-O', 'characterized-O', 'the-O', 'methylation-O', 'pattern-O', 'on-O', 'the-O', '5-O', 'side-O', 'of-O', 'the-O', 'CTG-O', 'repeat-O', 'in-O', 'the-O', 'DMPK-O', 'gene-O', 'of-O', 'normal-O', 'individuals-O', 'and-O', 'of-O', 'patients-O', 'affected-O', 'with-O', 'myotonic-B-SpecificDisease', 'dystrophy,-I-SpecificDisease', 'showing-O', 'expansions-O', 'of-O', 'the-O', 'repetitive-O', 'sequence.-O']
['The-O', 'gene-O', 'segment-O', 'analyzed-O', 'corresponds-O', 'to-O', 'the-O', 'genomic-O', 'SacI-HindIII-O', 'fragment-O', 'carrying-O', 'exons-O', '11-15.-O']
['There-O', 'is-O', 'constitutive-O', 'methylation-O', 'in-O', 'intron-O', '12-O', 'at-O', 'restriction-O', 'sites-O', 'of-O', 'SacII-O', 'and-O', 'HhaI,-O', 'localized-O', '1,-O', '159-1,-O', '232-O', 'bp-O', 'upstream-O', 'of-O', 'the-O', 'CTG-O', 'repeat,-O', 'whereas-O', 'most,-O', 'if-O', 'not-O', 'all,-O', 'of-O', 'the-O', 'other-O', 'sites-O', 'of-O', 'SacII,-O', 'HhaI,-O', 'and-O', 'HpaII-O', 'in-O', 'this-O', 'region-O', 'are-O', 'unmethylated,-O', 'in-O', 'normal-O', 'individuals-O', 'and-O', 'most-O', 'of-O', 'the-O', 'patients.-O']
['In-O', 'a-O', 'number-O', 'of-O', 'young-O', 'and-O', 'severely-O', 'affected-O', 'patients,-O', 'however,-O', 'complete-O', 'methylation-O', 'of-O', 'these-O', 'restriction-O', 'sites-O', 'was-O', 'found-O', 'in-O', 'the-O', 'mutated-O', 'allele.-O']
['In-O', 'most-O', 'of-O', 'these-O', 'patients,-O', 'the-O', 'onset-O', 'of-O', 'the-O', 'disease-B-DiseaseClass', 'was-O', 'congenital-B-SpecificDisease']
['Preliminary-O', 'in-O', 'vivo-O', 'footprinting-O', 'data-O', 'gave-O', 'evidence-O', 'for-O', 'protein-DNA-O', 'contact-O', 'in-O', 'normal-O', 'genes-O', 'at-O', 'an-O', 'Sp1-O', 'consensus-O', 'binding-O', 'site-O', 'upstream-O', 'of-O', 'the-O', 'CTG-O', 'repeat-O', 'and-O', 'for-O', 'a-O', 'significant-O', 'reduction-O', 'of-O', 'this-O', 'interaction-O', 'in-O', 'cells-O', 'with-O', 'a-O', 'hypermethylated-O', 'DMPK-O', 'gene..-O']
['Constitutional-O', 'RB1-gene-O', 'mutations-O', 'in-O', 'patients-O', 'with-O', 'isolated-O', 'unilateral-B-DiseaseClass', 'retinoblastoma.-I-DiseaseClass', 'In-O', 'most-O', 'patients-O', 'with-O', 'isolated-O', 'unilateral-O', 'retinoblastoma,-O', 'tumor-O', 'development-O', 'is-O', 'initiated-O', 'by-O', 'somatic-O', 'inactivation-O', 'of-O', 'both-O', 'alleles-O', 'of-O', 'the-O', 'RB1-O', 'gene.-O']
['However,-O', 'some-O', 'of-O', 'these-O', 'patients-O', 'can-O', 'transmit-O', 'retinoblastoma-B-SpecificDisease', 'predisposition-O', 'to-O', 'their-O', 'offspring.-O']
['To-O', 'determine-O', 'the-O', 'frequency-O', 'and-O', 'nature-O', 'of-O', 'constitutional-O', 'RB1-gene-O', 'mutations-O', 'in-O', 'patients-O', 'with-O', 'isolated-O', 'unilateral-B-DiseaseClass', 'retinoblastoma,-I-DiseaseClass', 'we-O', 'analyzed-O', 'DNA-O', 'from-O', 'peripheral-O', 'blood-O', 'and-O', 'from-O', 'tumor-O', 'tissue.-O']
['The-O', 'analysis-O', 'of-O', 'tumors-B-DiseaseClass', 'from-O', '54-O', '(71%)-O', 'of-O', '76-O', 'informative-O', 'patients-O', 'showed-O', 'loss-O', 'of-O', 'constitutional-O', 'heterozygosity-O', '(LOH)-O', 'at-O', 'intragenic-O', 'loci.-O']
['Three-O', 'of-O', '13-O', 'uninformative-O', 'patients-O', 'had-O', 'constitutional-O', 'deletions.-O']
['For-O', '39-O', 'randomly-O', 'selected-O', 'tumors,-B-DiseaseClass', 'SSCP,-O', 'hetero-duplex-O', 'analysis,-O', 'sequencing,-O', 'and-O', 'Southern-O', 'blot-O', 'analysis-O', 'were-O', 'used-O', 'to-O', 'identify-O', 'mutations.-O']
['Mutations-O', 'were-O', 'detected-O', 'in-O', '21-O', '(91%)-O', 'of-O', '23-O', 'tumors-B-DiseaseClass', 'with-O', 'LOH-O']
['In-O', '6-O', '(38%)-O', 'of-O', '16-O', 'tumors-B-DiseaseClass', 'without-O', 'LOH,-O', 'one-O', 'mutation-O', 'was-O', 'detected,-O', 'and-O', 'in-O', '9-O', '(56%)-O', 'of-O', 'the-O', 'tumors-B-DiseaseClass', 'without-O', 'LOH,-O', 'both-O', 'mutations-O', 'were-O', 'found.-O']
['Thus,-O', 'a-O', 'total-O', 'of-O', '45-O', 'mutations-O', 'were-O', 'identified-O', 'in-O', 'tumors-B-DiseaseClass', 'of-O', '36-O', 'patients.-O']
['Thirty-nine-O', 'of-O', 'the-O', 'mutations-including-O', '34-O', 'small-O', 'mutations,-O', '2-O', 'large-O', 'structural-O', 'alterations,-O', 'and-O', 'hypermethylation-O', 'in-O', '3-O', 'tumors-B-DiseaseClass', 'were-O', 'not-O', 'detected-O', 'in-O', 'the-O', 'corresponding-O', 'peripheral-O', 'blood-O', 'DNA.-O']
['In-O', '6-O', '(17%)-O', 'of-O', 'the-O', '36-O', 'patients,-O', 'a-O', 'mutation-O', 'was-O', 'detected-O', 'in-O', 'constitutional-O', 'DNA,-O', 'and-O', '1-O', 'of-O', 'these-O', 'mutations-O', 'is-O', 'known-O', 'to-O', 'be-O', 'associated-O', 'with-O', 'reduced-O', 'expressivity.-O']
['The-O', 'presence-O', 'of-O', 'a-O', 'constitutional-O', 'mutation-O', 'was-O', 'not-O', 'associated-O', 'with-O', 'an-O', 'early-O', 'age-O', 'at-O', 'treatment.-O']
['In-O', '1-O', 'patient,-O', 'somatic-O', 'mosaicism-O', 'was-O', 'demonstrated-O', 'by-O', 'molecular-O', 'analysis-O', 'of-O', 'DNA-O', 'and-O', 'RNA-O', 'from-O', 'peripheral-O', 'blood.-O']
['In-O', '2-O', 'patients-O', 'without-O', 'a-O', 'detectable-O', 'mutation-O', 'in-O', 'peripheral-O', 'blood,-O', 'mosaicism-O', 'was-O', 'suggested-O', 'because-O', '1-O', 'of-O', 'the-O', 'patients-O', 'showed-O', 'multifocal-O', 'tumors-O', 'and-O', 'the-O', 'other-O', 'later-O', 'developed-O', 'bilateral-O', 'retinoblastoma.-I-CompositeMention', 'In-O', 'conclusion,-O', 'our-O', 'results-O', 'emphasize-O', 'that-O', 'the-O', 'manifestation-O', 'and-O', 'transmissibility-O', 'of-O', 'retinoblastoma-B-SpecificDisease', 'depend-O', 'on-O', 'the-O', 'nature-O', 'of-O', 'the-O', 'first-O', 'mutation,-O', 'its-O', 'time-O', 'in-O', 'development,-O', 'and-O', 'the-O', 'number-O', 'and-O', 'types-O', 'of-O', 'cells-O', 'that-O', 'are-O', 'affected..-O']
['I1307K-O', 'APC-B-Modifier', 'and-O', 'hMLH1-O', 'mutations-O', 'in-O', 'a-O', 'non-Jewish-O', 'family-O', 'with-O', 'hereditary-B-SpecificDisease', 'non-polyposis-I-SpecificDisease', 'colorectal-I-SpecificDisease', 'cancer.-I-SpecificDisease', 'We-O', 'describe-O', 'a-O', 'French-O', 'Canadian-O', 'hereditary-B-SpecificDisease', 'non-polyposis-I-SpecificDisease', 'colorectal-I-SpecificDisease', 'cancer-O', '(HNPCC)-O', 'kindred-O', 'which-O', 'carries-O', 'a-O', 'novel-O', 'truncating-O', 'mutation-O', 'in-O', 'hMLH1.-O']
['Interestingly,-O', 'the-O', 'I1307K-O', 'APC-B-Modifier', 'polymorphism,-O', 'associated-O', 'with-O', 'an-O', 'increased-O', 'risk-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer,-I-SpecificDisease', 'is-O', 'also-O', 'present-O', 'in-O', 'this-O', 'family.-O']
['The-O', 'I1307K-O', 'polymorphism-O', 'has-O', 'previously-O', 'only-O', 'been-O', 'identified-O', 'in-O', 'individuals-O', 'of-O', 'self-reported-O', 'Ashkenazi-O', 'Jewish-O', 'origins.-O']
['In-O', 'addition,-O', 'in-O', 'this-O', 'family,-O', 'there-O', 'appears-O', 'to-O', 'be-O', 'no-O', 'relationship-O', 'between-O', 'the-O', 'I1307K-O', 'polymorphism-O', 'and-O', 'the-O', 'presence-O', 'or-O', 'absence-O', 'of-O', 'cancer.-B-DiseaseClass']
['Molecular-O', 'analysis-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'in-O', '205-O', 'families:-O', 'extended-O', 'genotype-phenotype-O', 'correlations-O', 'in-O', 'FAP-B-SpecificDisease', 'and-O', 'evidence-O', 'for-O', 'the-O', 'role-O', 'of-O', 'APC-B-Modifier', 'amino-O', 'acid-O', 'changes-O', 'in-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'predisposition.-O']
['BACKGROUND/AIMS-O', 'The-O', 'development-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'and-O', 'a-O', 'variable-O', 'range-O', 'of-O', 'extracolonic-O', 'manifestations-O', 'in-O', 'familial-B-SpecificDisease', 'adenomatous-I-SpecificDisease', 'polyposis-I-SpecificDisease', '(FAP)-O', 'is-O', 'the-O', 'result-O', 'of-O', 'the-O', 'dominant-O', 'inheritance-O', 'of-O', 'adenomatous-B-Modifier', 'polyposis-I-Modifier', 'coli-I-Modifier', '(APC)-B-Modifier', 'gene-O', 'mutations.-O']
['In-O', 'this-O', 'study,-O', 'direct-O', 'mutation-O', 'analysis-O', 'of-O', 'the-O', 'APC-B-Modifier', 'gene-O', 'was-O', 'performed-O', 'to-O', 'determine-O', 'genotype-phenotype-O', 'correlations-O', 'for-O', 'nine-O', 'extracolonic-O', 'manifestations-O', 'and-O', 'to-O', 'investigate-O', 'the-O', 'incidence-O', 'of-O', 'APC-B-Modifier', 'mutations-O', 'in-O', 'non-FAP-O', 'colorectal-B-SpecificDisease', 'cancer.-I-SpecificDisease', 'METHODS-O', 'The-O', 'APC-B-Modifier', 'gene-O', 'was-O', 'analysed-O', 'in-O', '190-O', 'unrelated-O', 'FAP-B-Modifier', 'and-O', '15-O', 'non-FAP-O', 'colorectal-B-SpecificDisease', 'cancer-O', 'patients-O', 'using-O', 'denaturing-O', 'gradient-O', 'gel-O', 'electrophoresis,-O', 'the-O', 'protein-O', 'truncation-O', 'test,-O', 'and-O', 'direct-O', 'sequencing.-O']
['RESULTS-O', 'Chain-O', 'terminating-O', 'signals-O', 'were-O', 'only-O', 'identified-O', 'in-O', 'patients-O', 'belonging-O', 'to-O', 'the-O', 'FAP-B-Modifier', 'group-O', '(105-O', 'patients).-O', 'Amino-O', 'acid-O', 'changes-O', 'were-O', 'identified-O', 'in-O', 'four-O', 'patients,-O', 'three-O', 'of-O', 'whom-O', 'belonged-O', 'to-O', 'the-O', 'non-FAP-O', 'group-O', 'of-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'patients.-O']
['Genotype-phenotype-O', 'correlations-O', 'identified-O', 'significant-O', 'differences-O', 'in-O', 'the-O', 'nature-O', 'of-O', 'certain-O', 'extracolonic-O', 'manifestations-O', 'in-O', 'FAP-B-Modifier', 'patients-O', 'belonging-O', 'to-O', 'three-O', 'mutation-O', 'subgroups.-O']
['CONCLUSIONS-O', 'Extended-O', 'genotype-phenotype-O', 'correlations-O', 'made-O', 'in-O', 'this-O', 'study-O', 'may-O', 'have-O', 'the-O', 'potential-O', 'to-O', 'determine-O', 'the-O', 'most-O', 'appropriate-O', 'surveillance-O', 'and-O', 'prophylactic-O', 'treatment-O', 'regimens-O', 'for-O', 'those-O', 'patients-O', 'with-O', 'mutations-O', 'associated-O', 'with-O', 'life-O', 'threatening-O', 'conditions.-O']
['This-O', 'study-O', 'also-O', 'provided-O', 'evidence-O', 'for-O', 'the-O', 'pathological-O', 'nature-O', 'of-O', 'amino-O', 'acid-O', 'changes-O', 'in-O', 'APC-B-Modifier', 'associated-O', 'with-O', 'both-O', 'FAP-B-SpecificDisease', 'and-O', 'non-FAP-O', 'colorectal-B-SpecificDisease', 'cancer-I-SpecificDisease', 'patients..-O']
['Detection-O', 'of-O', 'heterozygous-O', 'carriers-O', 'of-O', 'the-O', 'ataxia-telangiectasia-B-Modifier', '(ATM)-O', 'gene-O', 'by-O', 'G2-O', 'phase-O', 'chromosomal-O', 'radiosensitivity-O', 'of-O', 'peripheral-O', 'blood-O', 'lymphocytes.-O']
['In-O', 'ataxia-telangiectasia-B-SpecificDisease', '(A-T)-O', 'patients,-O', 'mutations-O', 'in-O', 'a-O', 'single-O', 'gene,-O', 'ATM,-O', 'result-O', 'in-O', 'an-O', 'autosomal-B-DiseaseClass', 'recessive-I-DiseaseClass', 'syndrome-I-DiseaseClass', 'that-O', 'embraces-O', 'a-O', 'variety-O', 'of-O', 'clinical-O', 'features-O', 'and-O', 'manifests-O', 'extreme-O', 'radiosensitivity-O', 'and-O', 'a-O', 'strong-O', 'pre-disposition-O', 'to-O', 'malignancy.-O', 'Heterozygotes-O', 'for-O', 'the-O', 'ATM-O', 'gene-O', 'have-O', 'no-O', 'clinical-O', 'expression-O', 'of-O', 'A-T-B-SpecificDisease', 'but-O', 'may-O', 'be-O', 'cancer-B-DiseaseClass', 'prone-O', 'with-O', 'a-O', 'moderate-O', 'increase-O', 'in-O', 'in-O', 'vitro-O', 'radiosensitivity.-O']
['We-O', 'performed-O', 'a-O', 'blind-O', 'chromosomal-O', 'analysis-O', 'on-O', 'G2-phase-O', 'lymphocytes-O', 'from-O', '7-O', 'unrelated-O', 'A-T-B-SpecificDisease', 'patients,-O', '13-O', 'obligate-O', 'A-T-B-SpecificDisease', 'heterozygotes-O', '(parents-O', 'of-O', 'the-O', 'patients),-O', 'and-O', '14-O', 'normal-O', 'controls-O', 'following-O', 'X-irradiation-O', 'with-O', '1-O', 'Gy-O', 'in-O', 'order-O', 'to-O', 'evaluate-O', 'this-O', 'cytogenetic-O', 'method-O', 'as-O', 'a-O', 'tool-O', 'for-O', 'detection-O', 'of-O', 'ATM-B-Modifier', 'carriers.-O']
['Both-O', 'A-T-B-Modifier', 'homozygotes-O', 'and-O', 'heterozygotes-O', 'showed-O', 'significantly-O', 'increased-O', 'levels-O', 'of-O', 'radiation-induced-O', 'chromatid-O', 'damage-O', 'relative-O', 'to-O', 'that-O', 'of-O', 'normal-O', 'controls.-O']
['These-O', 'results-O', 'show-O', 'that-O', 'the-O', 'G2-phase-O', 'chromosomal-O', 'radiosensitivity-O', 'assay-O', 'can-O', 'be-O', 'used-O', 'for-O', 'the-O', 'detection-O', 'of-O', 'A-T-B-SpecificDisease', 'heterozygotes.-O']
['In-O', 'combination-O', 'with-O', 'molecular-O', 'genetic-O', 'analyses,-O', 'this-O', 'test-O', 'may-O', 'be-O', 'of-O', 'value-O', 'in-O', 'studies-O', 'of-O', 'familial-B-SpecificDisease', 'and-O', 'sporadic-O', 'cancers-I-SpecificDisease', 'aimed-O', 'at-O', 'determination-O', 'of-O', 'the-O', 'potential-O', 'involvement-O', 'of-O', 'ATM-O', 'mutations-O', 'in-O', 'tumor-B-DiseaseClass', 'risk-O', 'or-O', 'development..-O']
['The-O', 'tumor-B-Modifier', 'suppressor-O', 'gene-O', 'Smad4/Dpc4-O', 'is-O', 'required-O', 'for-O', 'gastrulation-O', 'and-O', 'later-O', 'for-O', 'anterior-O', 'development-O', 'of-O', 'the-O', 'mouse-O', 'embryo.-O']
['Mutations-O', 'in-O', 'the-O', 'SMAD4/DPC4-O', 'tumor-B-Modifier', 'suppressor-O', 'gene,-O', 'a-O', 'key-O', 'signal-O', 'transducer-O', 'in-O', 'most-O', 'TGFbeta-related-O', 'pathways,-O', 'are-O', 'involved-O', 'in-O', '50%-O', 'of-O', 'pancreatic-B-SpecificDisease', 'cancers.-I-SpecificDisease', 'Homozygous-O', 'Smad4-O', 'mutant-O', 'mice-O', 'die-O', 'before-O', 'day-O', '7.-O']
['5-O', 'of-O', 'embryogenesis.-O']
['Mutant-O', 'embryos-O', 'have-O', 'reduced-O', 'size,-O', 'fail-O', 'to-O', 'gastrulate-O', 'or-O', 'express-O', 'a-O', 'mesodermal-O', 'marker,-O', 'and-O', 'show-O', 'abnormal-O', 'visceral-O', 'endoderm-O', 'development.-O']
['Growth-B-DiseaseClass', 'retardation-I-DiseaseClass', 'of-O', 'the-O', 'Smad4-deficient-B-Modifier', 'embryos-O', 'results-O', 'from-O', 'reduced-O', 'cell-O', 'proliferation-O', 'rather-O', 'than-O', 'increased-O', 'apoptosis.-O']
['Aggregation-O', 'of-O', 'mutant-O', 'Smad4-O', 'ES-O', 'cells-O', 'with-O', 'wild-type-O', 'tetraploid-O', 'morulae-O', 'rescues-O', 'the-O', 'gastrulation-O', 'defect.-O', 'These-O', 'results-O', 'indicate-O', 'that-O', 'Smad4-O', 'is-O', 'initially-O', 'required-O', 'for-O', 'the-O', 'differentiation-O', 'of-O', 'the-O', 'visceral-O', 'endoderm-O', 'and-O', 'that-O', 'the-O', 'gastrulation-O', 'defect-O', 'in-O', 'the-O', 'epiblast-O', 'is-O', 'secondary-O', 'and-O', 'non-cell-O', 'autonomous.-O']
['Rescued-O', 'embryos-O', 'show-O', 'severe-O', 'anterior-B-DiseaseClass', 'truncations,-I-DiseaseClass', 'indicating-O', 'a-O', 'second-O', 'important-O', 'role-O', 'for-O', 'Smad4-O', 'in-O', 'anterior-I-DiseaseClass', 'patterning-O', 'during-O', 'embryogenesis.-O']
['Genetic-O', 'basis-O', 'and-O', 'molecular-O', 'mechanism-O', 'for-O', 'idiopathic-B-DiseaseClass', 'ventricular-I-DiseaseClass', 'fibrillation.-I-DiseaseClass', 'Ventricular-O', 'fibrillation-O', 'causes-O', 'more-O', 'than-O', '300,-O', '000-O', 'sudden-O', 'deaths-O', 'each-O', 'year-O', 'in-O', 'the-O', 'USA-O', 'alone.-O']
['In-O', 'approximately-O', '5-12%-O', 'of-O', 'these-O', 'cases,-O', 'there-O', 'are-O', 'no-O', 'demonstrable-O', 'cardiac-O', 'or-O', 'non-cardiac-O', 'causes-O', 'to-O', 'account-O', 'for-O', 'the-O', 'episode,-O', 'which-O', 'is-O', 'therefore-O', 'classified-O', 'as-O', 'idiopathic-B-SpecificDisease', 'ventricular-I-SpecificDisease', 'fibrillation-I-SpecificDisease', '(IVF).-I-SpecificDisease', 'A-O', 'distinct-O', 'group-O', 'of-O', 'IVF-B-SpecificDisease', 'patients-O', 'has-O', 'been-O', 'found-O', 'to-O', 'present-O', 'with-O', 'a-O', 'characteristic-O', 'electrocardiographic-O', 'pattern.-O']
['Because-O', 'of-O', 'the-O', 'small-O', 'size-O', 'of-O', 'most-O', 'pedigrees-O', 'and-O', 'the-O', 'high-O', 'incidence-O', 'of-O', 'sudden-B-SpecificDisease', 'death,-O', 'however,-O', 'molecular-O', 'genetic-O', 'studies-O', 'of-O', 'IVF-O', 'have-O', 'not-O', 'yet-O', 'been-O', 'done.-O']
['Because-O', 'IVF-B-SpecificDisease', 'causes-O', 'cardiac-B-DiseaseClass', 'rhythm-O', 'disturbance,-I-DiseaseClass', 'we-O', 'investigated-O', 'whether-O', 'malfunction-O', 'of-O', 'ion-O', 'channels-O', 'could-O', 'cause-O', 'the-O', 'disorder-I-DiseaseClass', 'by-O', 'studying-O', 'mutations-O', 'in-O', 'the-O', 'cardiac-B-DiseaseClass', 'sodium-O', 'channel-O', 'gene-O', 'SCN5A.-O']
['We-O', 'have-O', 'now-O', 'identified-O', 'a-O', 'missense-O', 'mutation,-O', 'a-O', 'splice-donor-O', 'mutation,-O', 'and-O', 'a-O', 'frameshift-O', 'mutation-O', 'in-O', 'the-O', 'coding-O', 'region-O', 'of-O', 'SCN5A-O', 'in-O', 'three-O', 'IVF-O', 'families.-O']
['We-O', 'show-O', 'that-O', 'sodium-O', 'channels-O', 'with-O', 'the-O', 'missense-O', 'mutation-O', 'recover-O', 'from-O', 'inactivation-O', 'more-O', 'rapidly-O', 'than-O', 'normal-O', 'and-O', 'that-O', 'the-O', 'frameshift-O', 'mutation-O', 'causes-O', 'the-O', 'sodium-O', 'channel-O', 'to-O', 'be-O', 'non-functional.-O']
['Our-O', 'results-O', 'indicate-O', 'that-O', 'mutations-O', 'in-O', 'cardiac-O', 'ion-channel-O', 'genes-O', 'contribute-O', 'to-O', 'the-O', 'risk-O', 'of-O', 'developing-O', 'IVF-B-SpecificDisease..-O']
['Frequent-O', 'inactivation-O', 'of-O', 'PTEN/MMAC1-O', 'in-O', 'primary-B-SpecificDisease', 'prostate-B-SpecificDisease', 'cancer.-I-SpecificDisease', 'Sporadic-B-Modifier', 'prostate-B-SpecificDisease', 'carcinoma-I-SpecificDisease', 'is-O', 'the-O', 'most-O', 'common-O', 'male-O', 'cancer-I-SpecificDisease', 'in-O', 'the-O', 'Western-O', 'world,-O', 'yet-O', 'many-O', 'of-O', 'the-O', 'major-O', 'genetic-O', 'events-O', 'involved-O', 'in-O', 'the-O', 'progression-O', 'of-O', 'this-O', 'often-O', 'fatal-O', 'cancer-O', 'remain-O', 'to-O', 'be-O', 'elucidated.-O']
['Numerous-O', 'cytogenetic-O', 'and-O', 'allelotype-O', 'studies-O', 'have-O', 'reported-O', 'frequent-O', 'loss-O', 'of-O', 'heterozygosity-O', 'on-O', 'chromosomal-O', 'arm-O', '10q-O', 'in-O', 'sporadic-O', 'prostate-B-SpecificDisease', 'cancer.-I-SpecificDisease', 'Deletion-O', 'mapping-O', 'studies-O', 'have-O', 'unambiguously-O', 'identified-O', 'a-O', 'region-O', 'of-O', 'chromosome-O', '10q23-O', 'to-O', 'be-O', 'the-O', 'minimal-O', 'area-O', 'of-O', 'loss.-O']
['A-O', 'new-O', 'tumor-B-Modifier', 'suppressor-O', 'gene,-O', 'PTEN/MMAC1,-O', 'was-O', 'isolated-O', 'recently-O', 'at-O', 'this-O', 'region-O', 'of-O', 'chromosome-O', '10q23-O', 'and-O', 'found-O', 'to-O', 'be-O', 'inactivated-O', 'by-O', 'mutation-O', 'in-O', 'three-O', 'prostate-B-Modifier', 'cancer-I-Modifier', 'cell-O', 'lines.-O']
['We-O', 'screened-O', '80-O', 'prostate-B-SpecificDisease', 'tumors,-I-SpecificDisease', 'by-O', 'microsatellite-O', 'analysis-O', 'and-O', 'found-O', 'chromosome-O', '10q23-O', 'to-O', 'be-O', 'deleted-O', 'in-O', '23-O', 'cases.-O']
['We-O', 'then-O', 'proceeded-O', 'with-O', 'sequence-O', 'analysis-O', 'of-O', 'the-O', 'entire-O', 'PTEN/MMAC1-O', 'coding-O', 'region-O', 'and-O', 'tested-O', 'for-O', 'homozygous-O', 'deletion-O', 'with-O', 'new-O', 'intragenic-O', 'markers-O', 'in-O', 'these-O', '23-O', 'cases-O', 'with-O', '10q23-O', 'loss-O', 'of-O', 'heterozygosity-O']
['The-O', 'identification-O', 'of-O', 'the-O', 'second-O', 'mutational-O', 'event-O', 'in-O', '10-O', '(43%)-O', 'tumors-B-DiseaseClass', 'establishes-O', 'PTEN/MMAC1-O', 'as-O', 'a-O', 'main-O', 'inactivation-O', 'target-O', 'of-O', '10q-O', 'loss-O', 'in-O', 'sporadic-B-SpecificDisease', 'prostate-I-SpecificDisease', 'cancer.-I-SpecificDisease']
['Autosomal-B-SpecificDisease', 'dominant-I-SpecificDisease', 'neurohypophyseal-I-SpecificDisease', 'diabetes-I-SpecificDisease', 'insipidus-I-SpecificDisease', 'associated-O', 'with-O', 'a-O', 'missense-O', 'mutation-O', 'encoding-O', 'Gly23-->Val-O', 'in-O', 'neurophysin-O', 'II.-O']
['Autosomal-O', 'dominant-O', 'neurohypophyseal-B-SpecificDisease', 'diabetes-I-SpecificDisease', 'insipidus-I-SpecificDisease', '(ADNDI)-O', 'is-O', 'an-O', 'inherited-O', 'disease-O', 'caused-O', 'by-O', 'progressive-O', 'degeneration-O', 'of-O', 'the-O', 'magnocellular-O', 'neurons-O', 'of-O', 'the-O', 'hypothalamus-O', 'leading-O', 'to-O', 'decreased-O', 'ability-O', 'to-O', 'produce-O', 'the-O', 'hormone-O', 'arginine-O', 'vasopressin-O', '(AVP).-O', 'Affected-O', 'individuals-O', 'are-O', 'not-O', 'symptomatic-O', 'at-O', 'birth,-O', 'but-O', 'usually-O', 'develop-O', 'diabetes-I-SpecificDisease', 'insipidus-I-SpecificDisease', 'at-O', '1-6-O', 'yr-O', 'of-O', 'age.-O']
['The-O', 'genetic-O', 'locus-O', 'of-O', 'the-O', 'disease-O', 'is-O', 'the-O', 'AVP-neurophysin-O', 'II-O', '(NPII)-O', 'gene,-O', 'and-O', 'mutations-O', 'that-O', 'cause-O', 'ADNDI-B-DiseaseClass', 'have-O', 'been-O', 'found-O', 'in-O', 'both-O', 'the-O', 'signal-O', 'peptide-O', 'of-O', 'the-O', 'prepro-AVP-NPII-O', 'precursor-O', 'and-O', 'within-O', 'NPII-O', 'itself.-O']
['An-O', 'affected-O', 'girl-O', 'who-O', 'presented-O', 'at-O', '9-O', 'months-O', 'of-O', 'age-O', 'and-O', 'her-O', 'similarly-O', 'affected-O', 'younger-O', 'brother-O', 'and-O', 'father-O', 'were-O', 'all-O', 'found-O', 'to-O', 'have-O', 'a-O', 'novel-O', 'missense-O', 'mutation-O', '(G1758--O', '>-O', 'T)-O', 'encoding-O', 'the-O', 'amino-O', 'acid-O', 'substitution-O', 'Gly23--O', '>-O', 'Val-O', 'within-O', 'NPII.-O']
['The-O', 'mutation-O', 'was-O', 'confirmed-O', 'by-O', 'restriction-O', 'endonuclease-O', 'analysis.-O']
['A-O', 'T1-weighted-O', 'magnetic-O', 'resonance-O', 'imaging-O', 'of-O', 'the-O', 'fathers-O', 'pituitary-O', 'gland-O', 'demonstrates-O', 'an-O', 'attenuated-O', 'posterior-O', 'pituitary-O', 'bright-O', 'spot.-O']
['This-O', 'mutation-O', 'may-O', 'be-O', 'valuable-O', 'for-O', 'developing-O', 'models-O', 'of-O', 'dominantly-O', 'inherited-B-Modifier', 'neurodegeneration,-O', 'as-O', 'the-O', 'early-O', 'age-O', 'of-O', 'onset-O', 'of-O', 'symptoms-O', 'suggests-O', 'that-O', 'this-O', 'mutation-O', 'may-O', 'be-O', 'particularly-O', 'deleterious-O', 'to-O', 'the-O', 'magnocellular-O', 'neuron..-O']
['Schwartz-Jampel-B-SpecificDisease', 'syndrome-I-SpecificDisease', 'type-I-SpecificDisease', '2-I-SpecificDisease', 'and-O', 'Stuve-Wiedemann-B-SpecificDisease', 'syndrome:-I-SpecificDisease', 'a-O', 'case-O', 'for-O', '"lumping".-O', 'Recent-O', 'studies-O', 'demonstrated-O', 'the-O', 'existence-O', 'of-O', 'a-O', 'genetically-O', 'distinct,-O', 'usually-O', 'lethal-O', 'form-O', 'of-O', 'the-O', 'Schwartz-Jampel-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(SJS)-O', 'of-O', 'myotonia-B-DiseaseClass', 'and-O', 'skeletal-B-DiseaseClass', 'dysplasia,-I-DiseaseClass', 'which-O', 'we-O', 'called-O', 'SJS-O', 'type-I-SpecificDisease', '2.-I-SpecificDisease', 'This-O', 'disorder-O', 'is-O', 'reminiscent-O', 'of-O', 'another-O', 'rare-O', 'condition,-O', 'the-O', 'Stuve-Wiedemann-B-SpecificDisease', 'syndrome-I-SpecificDisease', '(SWS),-O', 'which-O', 'comprises-O', 'campomelia-B-DiseaseClass', 'at-O', 'birth-O', 'with-O', 'skeletal-B-DiseaseClass', 'dysplasia,-I-DiseaseClass', 'contractures,-I-DiseaseClass', 'and-O', 'early-O', 'death.-O', 'To-O', 'test-O', 'for-O', 'possible-O', 'nosologic-O', 'identity-O', 'between-O', 'these-O', 'disorders,-O', 'we-O', 'reviewed-O', 'the-O', 'literature-O', 'and-O', 'obtained-O', 'a-O', 'follow-up-O', 'of-O', 'the-O', 'only-O', 'two-O', 'surviving-O', 'patients,-O', 'one-O', 'with-O', 'SJS-O', 'type-I-SpecificDisease', '2-O', 'at-O', 'age-O', '10-O', 'years-O', 'and-O', 'another-O', 'with-O', 'SWS-O', 'at-O', 'age-O', '7-O', 'years.-O']
['Patients-O', 'reported-O', 'as-O', 'having-O', 'either-O', 'neonatal-O', 'SJS-B-SpecificDisease', 'or-O', 'SWS-B-SpecificDisease', 'presented-O', 'a-O', 'combination-O', 'of-O', 'a-O', 'severe,-O', 'prenatal-onset-O', 'neuromuscular-O', 'disorder,-O', '(with-O', 'congenital-O', 'joint-O', 'contractures,-O', 'respiratory-O', 'and-O', 'feeding-O', 'difficulties,-O', 'tendency-O', 'to-O', 'hyperthermia,-O', 'and-O', 'frequent-O', 'death-O', 'in-O', 'infancy)-O', 'with-O', 'a-O', 'distinct-O', 'campomelic-metaphyseal-O', 'skeletal-O', 'dysplasia.-O', 'The-O', 'similarity-O', 'of-O', 'the-O', 'clinical-O', 'and-O', 'radiographic-O', 'findings-O', 'is-O', 'so-O', 'extensive-O', 'that-O', 'these-O', 'disorders-O', 'appear-O', 'to-O', 'be-O', 'a-O', 'single-O', 'entity.-O']
['The-O', 'follow-up-O', 'observation-O', 'of-O', 'an-O', 'identical-O', 'and-O', 'unique-O', 'pattern-O', 'of-O', 'progressive-O', 'bone-B-DiseaseClass', 'dysplasia-I-DiseaseClass', 'in-O', 'the-O', 'two-O', 'patients-O', '(one-O', 'with-O', 'SJS-B-SpecificDisease', 'type-O', '2,-O', 'one-O', 'with-O', 'SWS-B-SpecificDisease)', 'surviving-O', 'beyond-O', 'infancy-O', 'adds-O', 'to-O', 'the-O', 'evidence-O', 'in-O', 'favor-O', 'of-O', 'identity.-O']
['The-O', 'hypothesis-O', 'that-O', 'SWS-B-SpecificDisease', 'and-O', 'SJS-B-SpecificDisease', 'type-O', '2-O', 'are-O', 'the-O', 'same-O', 'disorder-O', 'should-O', 'be-O', 'testable-O', 'by-O', 'molecular-O', 'methods..-O']