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

Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia

“…This overlap of repeat sizes in affected and non-affected individuals demonstrates the reduced penetrance previously suggested in SCA7. 19 Stevanin et al 24 recently demonstrated multiple origins of SCA7 in 41 families from several different ethnic backgrounds (Korea, Algeria, Morocco, Tunisia, USA, the UK, Italy, Belgium, France, Germany, Israel, South Africa, Brazil, Jamaica and the Philippines). The authors described four major haplotypes for the centromeric SCA7 region ( 3145 G/A/)/D3S1287/D3S3635) distributed in four distinct geographical areas, indicating regional founder effects.…”

“…This rare allele has so far only been reported on SCA7 chromosomes from one American SCA7 kindred of German origin (labelled allele 5 in the study referred to), but not on disease-bearing chromosomes from 32 other SCA7 families of various origins. 24 Of the seven control individuals who carried allele 3 for D3S1287, only two also carried allele A for the intragenic polymorphism 3145 G/A. As these individuals were heterozgyous for both markers, the maximum frequency for a possible A-3 haplotype in the non-affected Swedish population is as low as 0.75%.…”

“…Indeed, a recent linkage disequilibrium study by Stevanin et al revealed multiple origins of 41 SCA7 families of Asian, North African, European, Middle Eastern and South American origin. 24 Preliminary data indicated that in Sweden and Finland, unlike in other populations studied, SCA7 is by far the most common of all genetically verified dominant ataxias, suggesting the existence of a founder effect for the SCA7 mutation in these countries. To investigate this possibility we have performed an extensive haplotype study including all SCA7 families available in Scandinavia (Sweden, Norway, Denmark and Finland).…”

“…Families with SCA7 have been reported in families of various ethnic background, including kindreds from Europe (Belgium, Finland, France, Germany, Sweden and the UK), the Middle East (Israel), Africa (Algeria, Morocco, Libya, Tunisia and South Africa), North America (Caucasian-Americans and African-Americans), South America (Brazil), the West Indies (Jamaica) and Asia (Korea and the Philippines). [17][18][19][20][21][22][23][24] The presence of this relatively rare disease in such a variety of populations would indicate that the SCA7 mutation may have arisen several times, rather than all families sharing a common founder mutation. Indeed, a recent linkage disequilibrium study by Stevanin et al revealed multiple origins of 41 SCA7 families of Asian, North African, European, Middle Eastern and South American origin.…”

“…The intragenic SCA7 polymorphism 3145 G/A was amplified and analysed as described. 24 One sample from a French and an Algerian family each was included and genotyped in our laboratory for comparison of allele sizes to previous studies. 24 DNA from relatives of patients in families H, F4 and F7 was not available, therefore phase-unknown haplotypes are shown for these patients in Table 1.…”