Human Molecular Genetics, Vol 5, 923-932, Copyright © 1996 by Oxford University Press
S Igarashi, Y Takiyama, G Cancel, EA Rogaeva, H Sasaki, A Wakisaka, YX Zhou, H Takano, K Endo, K Sanpei, M Oyake, H Tanaka, G Stevanin, N Abbas, A Durr, EI Rogaev, R Sherrington, T Tsuda, M Ikeda, E Cassa, M Nishizawa, A Benomar, J Julien, J Weissenbach and S Tsuji
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.
ARTICLES
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
Department of Neurology, Niigata University, Japan.
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