Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCAII) waspreviously mapped by linkage analysis studies to chromosome 3p12- p21.1(SCA7). Positional cloning efforts have recently identified a novel gene,SCA7 , containing a translated CAG repeat, expanded in SCA7 patients. Wecloned the SCA7 gene from a yeast artificial chromosome (YAC) clone contigspanning the SCA7 candidate region. Using a combination of genomicsequencing and cosmid-based exon trapping, two expressed sequence tags wereidentified. Sequencing of the corresponding cDNA clones and RT-PCR analysisidentified the full- length SCA7 cDNA. Together, our sequence data definedthe intron/exon boundaries of the first two coding exons of the SCA7 gene,with the first exon containing the expanded CAG repeat. Further, sequencecomparison with the published SCA7 cDNA identified one additional putativeexon in the 5'-UTR region of the SCA7 gene. The SCA7 gene was mapped on theYAC contig in the 2.5 cM interval between D3S1600 and D3S1287. In oneextended Belgian SCA7 pedigree the expanded alleles ranged from 38 to atleast 55 repeats with allele lengths being inversely correlated with onsetage of ADCAII symptoms. The SCA7 repeats increased in length in successivegenerations. Normal alleles had from four to 18 repeats, with 10 repeatsbeing the most common allele.