Abstract
Mutations in VPS13A cause chorea-acanthocytosis (ChAc), an autosomal recessive neurodegenerative disorder. VPS13A is located in a tail-to-tail arrangement with GNA14 on chromosome 9q21. ChAc shows substantial allelic heterogeneity, with no single VPS13A mutation causing the majority of cases. We examined 11 patients in four French Canadian ChAc pedigrees for mutations in VPS13A. Affected members of three families were homozygous for a 37-kb deletion of the four terminal exons of VPS13A (EX70_EX73del). This deletion also encompasses the two terminal exons of GNA14. Two affected females in family 4 were homozygous for the splicing mutation 4242+1G>T. Remarkably, the affected males in this highly consanguineous pedigree were compound heterozygotes for EX70_EX73del and 4242+1G>T. PCR analysis of the deletion breakpoint junction revealed that an additional patient with French Canadian ancestry was heterozygous for the EX70_EX73del allele. The identification of a common 9q21 haplotype associated with EX70_EX73del in at least four apparently unrelated ChAc families implies that ChAc shows a founder effect in French Canadians, and that routine testing for EX70_EX73del in suspected ChAc cases may therefore be worthwhile in this population. The deletion breakpoint PCR described here will enable rapid identification of both homozygous and heterozygous carriers of EX70_EX73del.
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Abbreviations
- ChAc:
-
chorea-acanthocytosis
- DHPLC:
-
denaturing high-performance liquid chromatography
- FRAM:
-
free right-arm monomer
- MER:
-
medium reiteration frequency element
- OPMD:
-
oculopharyngeal muscular dystrophy
- SNP:
-
single nucleotide polymorphism
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Acknowledgements
The authors would like to thank the families for their participation, Lorne Lonie for DHPLC analysis and Carlos Singer and Igor Sibon for collection of patient samples and helpful discussions. This work was supported by funds from the Wellcome Trust (Wellcome Trust Prize Studentship 060886/Z/00/Z, held by C.D.-S.). C.D.-S. is currently supported by a European Molecular Biology Organisation postdoctoral fellowship (ref: ALTF166-2004). A.V.-B. is supported by a Marie Curie postdoctoral fellowship (ref: QLGA-CT-2001-51850). A.J. received funding from the Belgische Stichting Roeping/Foundation Belge de la Vocation and is currently receiving a fellowship from the Savoy Foundation for Epilepsy Research. E.A. was funded by a grant from the Canadian Institutes of Health Research. A.P.M. is a Wellcome Trust Principal Research Fellow (ref: 045093/Z/95). The experiments performed in this study comply with current UK laws.
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Dobson-Stone, C., Velayos-Baeza, A., Jansen, A. et al. Identification of a VPS13A founder mutation in French Canadian families with chorea-acanthocytosis. Neurogenetics 6, 151–158 (2005). https://doi.org/10.1007/s10048-005-0220-9
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DOI: https://doi.org/10.1007/s10048-005-0220-9