Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder
characterized by neurodegeneration of the cerebellum, spinal cord and
brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromo
some 6 containing the SCA1 locus was isolated in a yeast artificial ch
romosome contig and subcloned into cosmids. A highly polymorphic CAG r
epeat was identified in this region and was found to be unstable and e
xpanded in individuals with SCA1. There is a direct correlation betwee
n the size of the (CAG)n repeat expansion and the age-of-onset of SCA1
, with larger alleles occurring in juvenile cases. We also show that t
he repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefo
re the fifth genetic disorder to display a mutational mechanism involv
ing an unstable trinucleotide repeat.