Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG)

Abstract

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG), repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G3145TG/A3145TG). Four different haplotypes were found for centromeric markers (G3145TG/A3145TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same mural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.