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 (C)UNDER-BAR-GG (G)UNDER-BAR-GG POLYMORPHISM ON THE INTERGENERATIONAL INSTABILITY/

To investigate the mechanism of the meiotic instability of expanded CA G repeats in the gene for Machado-Joseph disease (MJD1), we analyzed t he CAG repeat sizes of 1036 single sperm from six individuals with Mac hado-Joseph disease (MJD), The segregation ratio between single sperm with an expanded allele and those with a normal allele is significantl y different (P < 0.0001) from the expected 1:1 segregation ratio, whic h demonstrates segregation distortion of expanded alleles in male meio sis, In single sperm from individuals with the [expanded (CAG)(n)-<(C) over bar GG>]/[normal (CAG)(n)-<(G)over bar GG>] genotype, significant ly greater instability of the CAG repeat was observed compared with si ngle sperm from individuals with the [expanded (CAG)(n)-<(C)over bar G G>]/[normal (CAG)(n)-<(C)over bar GG>] genotype (F-test, P < 0.001). T hese findings in single sperm confirm non-Mendelian transmission of th e MJD1 gene and the effect of the intragenic <(C)over bar GG>/<(G)over bar GG> polymorphism on the intergenerational instability of the CAG repeats in the MJD1 gene, which have been observed in clinical and gen etic studies, Our results indicate similarities and dissimilarities be tween MJD and Huntington's disease or myotonic dystrophy in terms of t he inter-allelic interaction, segregation distortions and size distrib ution of trinucleotide repeats in mutant alleles, Further study is req uired to determine whether there is a common mechanism underlying the instability of the triplet repeats in 'triplet repeat diseases'.