title: Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome?
abstract: Spinocerebellar ataxia type 6 (SCA6) is a common cause of dominantly inherited ataxia due to an expansion of the CAG repeat in the CACNA1A gene. Affected individuals from the same population share a common haplotype, raising the possibility that most SCA6 cases have descended from a small number of common founders across the globe. To test this hypothesis, we carried out haplotype analysis on SCA6 families from Europe, South America and the Far East, including an established de novo SCA6 expansion. A core CACNA1A disease haplotype was found in affected individuals across the globe. This was also present in the unaffected father of the de novo case, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies within a CpG island, which could act as a cis-acting element predisposing to repeat expansion as for other CAG/CTG repeat diseases. Polymorphic variation in this region may explain the high-risk haplotype found in SCA6 families.
authors.affiliation: Medical School,University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Takiyama
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Laura B
authors.initials: LB
authors.lastname: Jardim
authors.forename: Maria Luiza
authors.initials: ML
authors.lastname: Saraiva-Pereira
authors.forename: Kieren
authors.initials: K
authors.lastname: Lythgow
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morino
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002877:Chromosomes, Human / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D019295:Computational Biology; D005190:Family; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020754:Spinocerebellar Ataxias / Q000235:genetics*