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.

1. Hum Mol Genet. 1996 Jul;5(7):923-32.

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.

Igarashi S(1), Takiyama Y, Cancel G, Rogaeva EA, Sasaki H, Wakisaka A, Zhou YX,
Takano H, Endo K, Sanpei K, Oyake M, Tanaka H, Stevanin G, Abbas N, Dürr A,
Rogaev EI, Sherrington R, Tsuda T, Ikeda M, Cassa E, Nishizawa M, Benomar A,
Julien J, Weissenbach J, Wang GX, Agid Y, St George-Hyslop PH, Brice A, Tsuji S.

Author information:
(1)Department of Neurology, Niigata University, Japan.

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) 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.

DOI: 10.1093/hmg/5.7.923
PMID: 8817326 [Indexed for MEDLINE]

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