Canine hereditary ataxia in old english sheepdogs and gordon setters is associated with a defect in the autophagy gene encoding RAB24

PLoS Genet. 2014 Feb 6;10(2):e1003991. doi: 10.1371/journal.pgen.1003991. eCollection 2014 Feb.

Abstract

Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Cerebellar Cortex / pathology
  • Chromosome Mapping
  • Dog Diseases / genetics*
  • Dog Diseases / pathology
  • Dogs
  • Genome-Wide Association Study*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mice
  • Mutation
  • Polymorphism, Single Nucleotide
  • Spinocerebellar Degenerations / etiology
  • Spinocerebellar Degenerations / genetics*
  • rab GTP-Binding Proteins / genetics*

Substances

  • RAB24 protein, human
  • rab GTP-Binding Proteins

Grants and funding

This work was supported by grants CHF 0407 and 0925, from the American Kennel Club Canine Health Foundation (www.akcchf.org). It was also supported by the Old English Sheepdog Club of America, the TarTan Gordon Setter Club and the OFA CHIC DNA Repository. KLT was funded by a EURYI from the European Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.