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 INSTABILITYOF THE CAG REPEAT

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerativ e disorder caused by unstable expansion of a CAG repeat in the MJD1 ge ne at 14q32.1. To identify elements affecting the intergenerational in stability of the CAG repeat, we investigated whether the CGG/GGG polym orphism at the 3' end of the CAG repeat affects intergenerational inst ability 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. Multipl e stepwise logistic regression analysis revealed that the relative ris k for a large intergenerational change in the number of CAG repeat uni ts (<-2 or >2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of pa ternal 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 w ith the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in t hat of transmission from a parent with the [expanded (CAG)n-CGG]/[norm al (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes . The combination of paternal transmission and the [expanded (CAG)n-CG G]/[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 t ransmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expa nded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest t hat an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.