Document Detail

Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat.
MedLine Citation:
PMID:  8817326     Owner:  NLM     Status:  MEDLINE    
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.
S Igarashi; Y Takiyama; G Cancel; E A Rogaeva; H Sasaki; A Wakisaka; Y X Zhou; H Takano; K Endo; K Sanpei; M Oyake; H Tanaka; G Stevanin; N Abbas; A Dürr; E I Rogaev; R Sherrington; T Tsuda; M Ikeda; E Cassa; M Nishizawa; A Benomar; J Julien; J Weissenbach; G X Wang; Y Agid; P H St George-Hyslop; A Brice; S Tsuji
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human molecular genetics     Volume:  5     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  1996 Jul 
Date Detail:
Created Date:  1997-01-16     Completed Date:  1997-01-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  923-32     Citation Subset:  IM    
Department of Neurology, Niigata University, Japan.
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MeSH Terms
Chromosomes, Human, Pair 14 / genetics*
Gene Frequency
Machado-Joseph Disease / ethnology,  genetics*
Polymorphism, Genetic*
Sex Factors
Trinucleotide Repeats / genetics*

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