Genetics of the SCA6 gene in a large family segregating an autosomal dominant "pure" cerebellar ataxia

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar de generation caused by the expansion of a CAG trinucleotide repeat in the CAC NA1A gene. Mutations in patients are characterised by expanded alleles of b etween 21 and 30 repeat units and by extreme gonadal stability when transmi tted from parents to children. We have investigated the SCA6 mutation in a large Spanish kindred in which previously reported spinocerebellar SCA gene s and loci had been excluded. We observed a 23 CAG repeat-expanded allele i n the 13 clinically affected subjects and in three out of 10 presymptomatic at risk subjects. Transmission of the mutant allele was stable in six pare nt to child pairs and in 29 meioses through the pedigree. Linkage analysis with the SCA6-CAG polymorphism and marker D19S221 confirmed the location of SCA6 on chromosome 19p13. The molecular findings in this large family conf irm the expansion of the CAG repeat in the CACNA1A gene as the cause of SCA 6 and the high meiotic stability of the repeat.