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 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.