title: Canine hereditary ataxia in old english sheepdogs and gordon setters is associated with a defect in the autophagy gene encoding RAB24.
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.
authors: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Caryline
authors: C
authors: Agler
authors: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Dahlia M
authors: DM
authors: Nielsen
authors: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Ganokon
authors: G
authors: Urkasemsin
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors: Andrew
authors: A
authors: Singleton
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America ; Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America.
authors: Noriko
authors: N
authors: Tonomura
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Snaevar
authors: S
authors: Sigurdsson
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Ruqi
authors: R
authors: Tang
authors: Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Keith
authors: K
authors: Linder
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors: Sampath
authors: S
authors: Arepalli
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors: Dena
authors: D
authors: Hernandez
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America ; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Kerstin
authors: K
authors: Lindblad-Toh
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors: Joyce
authors: J
authors: van de Leemput
authors: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, United States of America ; Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Alison
authors: A
authors: Motsinger-Reif
authors: Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States of America.
authors: Dennis P
authors: DP
authors: O'Brien
authors: Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America.
authors: Jerold
authors: J
authors: Bell
authors: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Tonya
authors: T
authors: Harris
authors: VCA Veterinary Referral Associates, Gaithersbrug, Maryland, United States of America.
authors: Steven
authors: S
authors: Steinberg
authors: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America ; Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Natasha J
authors: NJ
authors: Olby
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002525:Cerebellar Cortex / Q000473:pathology; D002874:Chromosome Mapping; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013132:Spinocerebellar Degenerations / Q000209:etiology / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: C514248:RAB24 protein, human; D020691:rab GTP-Binding Proteins