RELATIONSHIP OF (CAG)NC CONFIGURATION TO REPEAT INSTABILITY OF THE MACHADO-JOSEPH-DISEASE GENE

The mutation responsible for Machado-Joseph disease (MJD) has been ide ntified as an expansion of a CAG trinucleotide repeat in a novel gene on chromosome 14q32.1. The CAG repeat tract is followed by C or G, and alleles are thereby divided into two types on the basis of molecular configuration, (CAG)nC and (CAG)nG, We have studied the relationship b etween the repeat length and the configuration in 38 patients from 28 Japanese families with MJD, and 31 unrelated normal Japanese subjects. The CAG repeat length in 100 normal alleles ranged from 13 to 37 repe ats, while 38 MJD patients had one expanded allele with 64 to 84 repea ts, Surprisingly, the expanded alleles had exclusively the (CAG)nC con figuration, while both (CAG)nC and (CAG)nG were seen in normal alleles from MJD and control subjects. Furthermore, in normal alleles, the CA G repeat tract was significantly longer in (CAG)nC than in (CAG)nG, Th ese findings suggest that the (CAG)nC configuration is related to repe at instability of the MJD gene.