SEQUENCE VARIATION AND SIZE RANGES OF CAG REPEATS IN THE MACHADO-JOSEPH DISEASE, SPINOCEREBELLAR ATAXIA TYPE-1 AND ANDROGEN RECEPTOR GENES

A subgroup of trinucleotide repeat diseases result from abnormal expan sions of CAG repeats which are translated into polyglutamine stretches . As yet there is little understanding of how the polyglutamines funct ion either normally, or when expanded. We have investigated these sequ ences in the Machado-Joseph disease, androgen receptor and spinocerebe llar ataxia type 1 genes in humans and other primates. None of the 748 normal chromosomes that were examined had more than 34 uninterrupted glutamine codons in the Machado-Joseph disease gene. Similarly, no nor mal alleles with more than 39 uninterrupted glutamine codons have been reported for the other disease genes associated with polyglutamine ex pansions. Sequence analyses of the repeats in primates revealed shorte r polyglutamine stretches in some of the non-human primates at all thr ee loci and marked diversions from the expected polyglutamines in the orang-utan Machado-Joseph gene and in the marmoset spinocerebellar ata xia type 1 gene. These data suggest that conservation of these polyglu tamine stretches may not always be necessary for normal gene function.