OMIA 001913-9615 : Ataxia, cerebellar, juvenile to adolescent, RAB24-related in Canis lupus familiaris

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:

Symbol Description Species Chr Location OMIA gene details page Other Links
RAB24 RAB24, member RAS oncogene family Canis lupus familiaris 4 NC_006586.3 (36055190..36059945) RAB24 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Gordon Setter Old English Sheepdog Ataxia, cerebellar, in Old English Sheepdogs and Gordon Setters RAB24 missense CanFam3.1 4 g.36055678A>C c.113A>C p.Q38P 2014 24516392 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2014 Agler, C., Nielsen, D.M., Urkasemsin, G., Singleton, A., Tonomura, N., Sigurdsson, S., Tang, R., Linder, K., Arepalli, S., Hernandez, D., Lindblad-Toh, K., van de Leemput, J., Motsinger-Reif, A., O'Brien, D.P., Bell, J., Harris, T., Steinberg, S., Olby, N.J. :
Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24. PLoS Genet 10:e1003991, 2014. Pubmed reference: 24516392. DOI: 10.1371/journal.pgen.1003991.
2000 Steinberg, K.S., Van, Winkle, T., Bell, J.S., de, Lahunta, A. :
Cerebellar degeneration in Old English Sheepdogs Journal of the American Veterinary Medical Association 217:1162-1165, 2000. Pubmed reference: 11043686.
1985 Troncoso, J.C., Cork, L.C., Price, D.L. :
Canine inherited ataxia: ultrastructural observations. J Neuropathol Exp Neurol 44:165-75, 1985. Pubmed reference: 3973637.
1984 Tiemeyer, M.J., Singer, H.S., Troncoso, J.C., Cork, L.C., Coyle, J.T., Price, D.L. :
Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of Gordon Setters. J Neuropathol Exp Neurol 43:580-91, 1984. Pubmed reference: 6502189.
1981 Steinberg, H.S., Troncoso, J.C., Cork, L.C., Price, D.L. :
Clinical features of inherited cerebellar degeneration in Gordon Setters Journal of the American Veterinary Medical Association 179:886-890, 1981. Pubmed reference: 7341602.
1980 Delahunta, A., Fenner, W.R., Indrieri, P.J., Mellick, P.W., Gardner, S., Bell, J.S. :
Hereditary cerebellar cortical abiotrophy in the Gordon Setter Journal of the American Veterinary Medical Association 177:538-541, 1980. Pubmed reference: 7440348.

Edit History


  • Created by Frank Nicholas on 18 Feb 2014
  • Changed by Frank Nicholas on 18 Feb 2014
  • Changed by Tosso Leeb on 19 Jan 2017
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  • Changed by Tosso Leeb on 07 Jul 2017