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

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerativedisorder caused by unstable expansion of a CAG repeat in the MJD1 gene at14q32.1. To identify elements affecting the intergenerational instabilityof the CAG repeat, we investigated whether the CGG/GGG polymorphism at the3' end of the CAG repeat affects intergenerational instability of the CAGrepeat. The [expanded (CAG)n-CGG]/[normal (CAG)n- GGG] haplotypes werefound to result in significantly greater instability of the CAG repeatcompared to the [expanded (CAG)n- CGG]/[normal (CAG)n-CGG] or [expanded(CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logisticregression analysis revealed that the relative risk for a largeintergenerational 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 paternaltransmission 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 oftransmission from a parent with the [expanded (CAG)n-CGG]/[normal(CAG)n-CGG] or [expanded (CAG)n- GGG]/[normal (CAG)n-GGG] haplotypes. Thecombination 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) increasein 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- allelicinteraction is involved in the intergenerational instability of theexpanded CAG repeat.