GAMETIC AND SOMATIC TISSUE-SPECIFIC HETEROGENEITY OF THE EXPANDED SCA1 CAG REPEAT IN SPINOCEREBELLAR ATAXIA TYPE-1

Spinocerebellar ataxia type 1 is associated with expansion of an unsta ble CAG repeat within the SCA1 gene. Male gametic heterogeneity of the expanded repeat is demonstrated using single sperm and low-copy genom e analysis. Low-copy genome analysis of peripheral blood also reveals somatic heterogeneity of the expanded SCA1 allele, thus establishing m itotic instability at this locus. Comparative analysis of a large norm al allele and a small affected allele suggests a role of midstream CAT interspersions in stabilizing long (CAG)(n) stretches. Within the bra in, tissue-specific mosaicism of the expanded allele is also observed. The differences in SCA1 allele heterogeneity between sperm and blood and within the brain parallels the findings in Huntington disease, sug gesting that both disorders share a common mechanism for tissue-specif ic instability.