Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability

To investigate the mechanism of the meiotic instability of expanded CAGrepeats in the gene for Machado-Joseph disease (MJD1), we analyzed the CAGrepeat sizes of 1036 single sperm from six individuals with Machado- Josephdisease (MJD). The segregation ratio between single sperm with an expandedallele and those with a normal allele is significantly different (P<0.0001) from the expected 1:1 segregation ratio, which demonstratessegregation distortion of expanded alleles in male meiosis. In single spermfrom individuals with the [expanded (CAG)n- CGG]/[normal (CAG)n-GGG]genotype, significantly greater instability of the CAG repeat was observedcompared with single sperm from individuals with the [expanded(CAG)n-CGG]/[normal (CAG)n-CGG] genotype (F-test, P <0.001). Thesefindings in single sperm confirm non-Mendelian transmission of the MJD1gene and the effect of the intragenic CGG/GGG polymorphism on theintergenerational instability of the CAG repeats in the MJD1 gene, whichhave been observed in clinical and genetic studies. Our results indicatesimilarities and dissimilarities between MJD and Huntington's disease ormyotonic dystrophy in terms of the inter-allelic interaction, segregationdistortions and size distribution of trinucleotide repeats in mutantalleles. Further study is required to determine whether there is a commonmechanism underlying the instability of the triplet repeats in 'tripletrepeat diseases'.