Abstract
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 materialThe online version of this article (doi:10.1007/s00335-014-9547-6) contains supplementary material, which is available to authorized users.
Highlights
Spinocerebellar ataxia in the Italian Spinone (SCAIS) is a progressive neurodegenerative disease characterised by hypermetria, in the pelvic limbs, truncal ataxia and impaired balance
Neurological characteristics of SCAIS include a wide-based stance, spinocerebellar ataxia characterised by thoracic limb hypermetria, pelvic limb hyperflexion, truncal swaying, impaired balance, pendular nystagmus and absent menace response bilaterally
We have identified a GAA repeat expansion in intron 35 ITPR1 which is strongly associated with autosomal recessive SCAIS
Summary
Spinocerebellar ataxia in the Italian Spinone (SCAIS) is a progressive neurodegenerative disease characterised by hypermetria, in the pelvic limbs, truncal ataxia and impaired balance. Clinical signs start to appear at four months of age and progress to a degree of dysfunction which leads to euthanasia of affected dogs at one year of age on average. SCAIS was acknowledged in the veterinary literature as a brief clinical communication in 1996 (Wheeler and Rusbridge 1996), and has been reported anecdotally in a number of countries including Italy, UK, USA and Denmark. With no new cases reported since the launch of a linkage based DNA test at the Animal Health Trust in 2008, enabling breeders to identify heterozygous carriers in their breeding lines. Forman et al : Spinocerebellar ataxia in the Italian Spinone dog
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