Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 612415 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Canine hereditary ataxia

Species-specific description: Ataxia is characterized by uncoordinated movements and represents a relatively non-specific clinical sign. This entry describes an ataxia form that is caused by a genetic variant in the RAB24 gene. Phenotypically related ataxias in dogs may also be caused by variants in the ATP1B2, CAPN1, GRM1, ITPR1, KCNJ10, SEL1L, SNX14, and SPTBN2 genes. Thus locus heterogeneity for this phenotype must be considered.

Mapping: From a genome scan of "Forty-eight related Old English Sheepdogs, including eight affected dogs", each genotyped with 311 microsatellites (yielding 264 informative markers), Agler et al. (2014) mapped this disorder to a 17MB region on chromosome CFA4. Fine-mapping with additional markers confirmed but did not narrow this region. The same authors then conducted a GWAS on the same 48 dogs plus 6 additional affected animals from the same breed, each genotyped with the "Illumina Infinium CanineSNP20 Beadchip (22 dogs)" or "CanineHDBeadchip (32 dogs)" (yielding 12,986 informative SNPs), narrowing the candidate region on CFA4 to between 36Mb and 42Mb. Sequencing of this candidate region on CFA4 via targeted sequence capture in three affected and three non-affected dogs, followed by filtering of the identified variants, narrowed down the field to six missense mutations in five genes.

Molecular basis: Sanger sequencing of the six candidate variants (see Mapping section above) in additional cases and controls revealed the most likely causal mutation to be an "RAB24 SNP polymorphism [which] was an A to C transversion located at position 113 [c.113A>C] in the first of its eight exons . . . [which] produced an amino acid change from glutamine (Q) to proline (P) at position 38" (p.Q38P). Sequencing of the RAB24 exons in affected dogs from other breeds revealed the same allele to be potentially causative in Gordon Setters. Subsequent sequencing and SNP genotyping within this breed provided strong supportive evidence for the c.113A>C, p.Q38P mutation being causal in this breed.

Clinical features: "The clinical phenotype is identical in both breeds with an onset of cerebellar ataxia first noted in juvenile to young adult dogs aged from six months to four years. Dogs develop pronounced hypermetria, a truncal sway and intention tremor, and signs progress to cause severe gait disturbances. Cerebellar atrophy can be identified by magnetic resonance imaging (MRI)" (Agler et al. 2014)

Pathology: As reported by Agler et al. (2014), "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."

Prevalence: Alger et al. (2014) reported an allele frequency of 14.3% in a sample of 630 Old English Sheepdogs and 22.2% in a sample of 90 Gordon Setters. None of 194 dogs from 43 other breeds had the mutant allele.

Breeds: Gordon Setter, Old English Sheepdog.

Associated gene: