Spinocerebellar Ataxia Type 8: Molecular Genetic Comparisonsand Haplotype Analysis of 37 Families with Ataxia
Autor: | Melinda L. Moseley, William K. Seltzer, Joline C. Dalton, T. Ashizawa, Massimo Pandolfo, John W. Day, Nicholas T. Potter, Laura P.W. Ranum, John B. Vincent, Kathy Gardner, Aubrey Milunsky, Yoshio Ikeda, Mikio Shoji, Thomas D. Bird |
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Rok vydání: | 2004 |
Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities RNA Untranslated Ataxia Population Nerve Tissue Proteins Biology 03 medical and health sciences 0302 clinical medicine Chromosome Segregation Genetic variation medicine Genetics Humans Spinocerebellar Ataxias Genetic Predisposition to Disease Genetics(clinical) education Molecular Biology Genetics (clinical) 030304 developmental biology 0303 health sciences education.field_of_study Haplotype Genetic Variation Articles medicine.disease Penetrance Pedigree White (mutation) Genetics Population Haplotypes Psychotic Disorders Case-Control Studies Spinocerebellar ataxia Female RNA Long Noncoding medicine.symptom Trinucleotide Repeat Expansion Trinucleotide repeat expansion 030217 neurology & neurosurgery Microsatellite Repeats |
Zdroj: | The American Journal of Human Genetics. 75(1):3-16 |
ISSN: | 0002-9297 |
DOI: | 10.1086/422014 |
Popis: | We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis. |
Databáze: | OpenAIRE |
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