Mitotic and meiotic instability of the CAG trinucleotide repeat in spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is an autosomal, dominantly inherited neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion in the ataxin-1 gene located on chromosome 6p22-p23. The expanded CAG repeat is unstable during transmission, and a variation in the CAG repeat length has been found in different tissues, including sperm samples from affected males. In order further to examine the mitotic and meiotic instability of the (CAG)n stretch we have performed single sperm and low-copy genome analysis in SCA1 patients and asymptomatic carriers. A pronounced variation in the size of the expanded allele was found in sperm cells and peripheral blood leucocytes, with a higher degree of instability seen in the sperm cells, where an allele with 50 repeat units was contracted in 11.8%, further expanded in 63.5% and unchanged in 24.6% of the single sperm analysed. We found a low instability of the normal alleles; the normal alleles from the individuals carrying a CAG repeat expansion were significantly more unstable than the normal alleles from the control individuals (P<0.001), indicating an interallelic interaction between the expanded and the normal alleles.