Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1

Spinocerebellar ataxia in the Italian Spinone dog breed is characterised by a progressive gait abnormality that manifests from approximately 4 months of age. The disorder shows an autosomal recessive mode of inheritance, and affected individuals are usually euthanized by one year of age on welfare grounds due to an inability to ambulate. Using a homozygosity mapping technique with six cases and six controls, we mapped the disease locus to chromosome 20 of the canine genome. Linkage analysis across an extended pedigree confirmed the association, with microsatellite C20.374 achieving a maximal LOD score of 4.41. All five genes within the disease-associated interval were exon resequenced, although no exonic candidate mutations were identified. A targeted resequencing approach was therefore adopted to sequence the entire disease-associated interval. Analysis of the sequencing data revealed a GAA repeat expansion in intron 35 of ITPR1, which was homozygous in all cases and heterozygous in obligate carriers. Partial impairment of cerebellar ITPR1 expression in affected dogs was demonstrated by immunohistochemistry. Given the association of ITPR1 mutations with spinocerebellar ataxia (SCA) type 15 (also designated SCA16) in humans and that an intronic GAA repeat expansion has been shown to cause Friedreich ataxia, the repeat expansion is an excellent candidate for the cause of spinocerebellar ataxia in the Italian Spinone. This finding represents the first naturally occurring pathogenic intronic GAA repeat expansion in a non-human species and a novel mechanism for ITPR1 associated spinocerebellar ataxia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00335-014-9547-6) contains supplementary material, which is available to authorized users.