Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24

• DOI: 10.1371/journal.pgen.1003991
• Publication Date: 2014-02-06T21:48:35Z
• Authors: Caryline Agler; Dahlia M. Nielsen; Ganokon Urkasemsin; Andrew Singleton; Noriko Tonomura; Snaevar Sigurdsson; Ruqi Tang; Keith Linder; Sampath Arepalli; Dena Hernandez; Kerstin Lindblad-Toh; Joyce van de Leemput; Alison Motsinger-...; Dennis P. O'Brien; Jerold Bell; Tonya Harris; Steven Steinberg; Natasha J. Olby
• Keywords: 0301 basic medicine; Chromosome Mapping; High-Throughput Nucleotide Sequencing; Genetics and Genomics; Genetik och genomik; QH426-470; Polymorphism, Single Nucleotide; 630; 3. Good health; Cerebellar Cortex; Mice; 03 medical and health sciences; Dogs; rab GTP-Binding Proteins; Mutation; Genetics; Autophagy; Animals; Humans; Dog Diseases; Genetik; Research Article; Genome-Wide Association Study; Spinocerebellar Degenerations

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