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

Forman OP, De Risio L, Matiasek K, Platt S, Mellersh C - Mamm. Genome (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK, oliver.forman@aht.org.uk.

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.

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Related in: MedlinePlus

Plot of chromosome 20 LOD scores associated with CFA20 markers when genotyped across an extended IS pedigree consisting of 13 SCA cases and 47 controls. The maximal LOD score was 4.41 at 15.60 Mb
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Fig1: Plot of chromosome 20 LOD scores associated with CFA20 markers when genotyped across an extended IS pedigree consisting of 13 SCA cases and 47 controls. The maximal LOD score was 4.41 at 15.60 Mb

Mentions: Linkage analysis across an extended pedigree containing 13 cases and 47 controls, including 16 obligate carriers, was performed to confirm the association of SCA to chromosome 20. Data from 22 microsatellite markers across chromosome 20 were analysed using the MLINK software package, with marker C20.374 achieving a maximal logarithm of odds (LOD) score of 4.41 at θ 0 (Fig. 1), confirming linkage.Fig. 1


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

Forman OP, De Risio L, Matiasek K, Platt S, Mellersh C - Mamm. Genome (2014)

Plot of chromosome 20 LOD scores associated with CFA20 markers when genotyped across an extended IS pedigree consisting of 13 SCA cases and 47 controls. The maximal LOD score was 4.41 at 15.60 Mb
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4305091&req=5

Fig1: Plot of chromosome 20 LOD scores associated with CFA20 markers when genotyped across an extended IS pedigree consisting of 13 SCA cases and 47 controls. The maximal LOD score was 4.41 at 15.60 Mb
Mentions: Linkage analysis across an extended pedigree containing 13 cases and 47 controls, including 16 obligate carriers, was performed to confirm the association of SCA to chromosome 20. Data from 22 microsatellite markers across chromosome 20 were analysed using the MLINK software package, with marker C20.374 achieving a maximal logarithm of odds (LOD) score of 4.41 at θ 0 (Fig. 1), confirming linkage.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK, oliver.forman@aht.org.uk.

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.

Show MeSH
Related in: MedlinePlus