OMIA 001820-9615 : Ataxia, spinocerebellar, CAPN1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 616907

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Spinocerebellar ataxia

Species-specific name: spinocerebellar ataxia, hereditary ataxia

Species-specific symbol: SCA

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 CAPN1 gene. A phenotypically closely related ataxia in Russell group terriers and Smooth-Haired Fox Terriers is caused by a variant in the KCNJ10 gene. Other hereditary ataxias in dogs may be caused by variants in the ATP1B2, GRM1, ITPR1, KCNJ10, RAB24, SEL1L, SNX14, and SPTBN2 genes. Thus heterogeneity for this phenotype must be considered.

Mapping: By conducting a GWAS on 16 affected and 16 control Parson Russell Terriers, each genotyped with the Illumina CanineHD (yielding 126,225 informative SNPs), Forman et al. (2013) mapped this disorder to a single peak on chromosome CFA18. Homozygosity mapping defined this as the 1.8 Mb region "chr18:53,533,360–55,418,743", which contains 91 genes. Subsequent to the discovery in dogs, similar CAPN1 variants were identified in human patients with autosomal recessive hereditary spastic paraplegia and Capn1 knock-out mice were also shown to have a comparable phenotype.

Molecular basis: Target-enriched deep sequencing of the 1.8Mb candidate region (see Mapping section) and checking identified mutations in various samples of dogs eventually enabled Forman et al. (2013) to claim "a missense mutation ([c.344G>A;] p.Cys115Tyr) in the gene encoding the large subunit of calcium dependent cysteine protease, μ-calpain (CAPN1)" as "a provocative candidate for the cause of SCA in the PRT [Parson Russell Terrier] and a novel potential cause of ataxia in humans."

Clinical features: The clinics and pathology of "hereditary ataxia" in Jack Russell and Parson Russell Terriers were mostly studied before the different causative variants in CAPN1 (this entry) and KCNJ10 (see the related entry 002089-9615) were identified. It is therefore not fully clear which genetic form of ataxia was investigated in the earlier publications. It is likely that there are even more genetically distinct forms of ataxia present in Russell group terriers.

The CAPN1 form of this disease manifests as a slowly progressing pelvic limb incoordination, with an onset usually at 2 to 9 months of age. As the disease progresses a characteristic “dancing” or “prancing” gait is displayed, especially affecting the pelvic limbs. The age at onset of Parson Russell Terrier cases that were used to identify the CAPN1:p.Cys115Tyr variant ranged between 7-12 months. (Forman et al. 2013). The supplementary video S1 in this publication illustrates the clinical phenotype.

Breeds: Jack Russell Terrier, Parson Russell Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CAPN1 calpain 1, (mu/I) large subunit Canis lupus familiaris 18 NC_006600.3 (52010831..51983266) CAPN1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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
Parson Russell Terrier Ataxia, spinocerebellar KCNJ10 missense c.344G>A p.C115Y 2013 23741357
Russell Terrier Spinocerebellar ataxia with myokymia, seizures, or both KCNJ10 missense c.627C>G p.I209M 2014 24708069
Malinois Ataxia, spinocerebellar KCNJ10 missense c.986T>C p.L329P 2017 27966545

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.
2016 Gan-Or, Z., Bouslam, N., Birouk, N., Lissouba, A., Chambers, D.B., Vérièpe, J., Androschuk, A., Laurent, S.B., Rochefort, D., Spiegelman, D., Dionne-Laporte, A., Szuto, A., Liao, M., Figlewicz, D.A., Bouhouche, A., Benomar, A., Yahyaoui, M., Ouazzani, R., Yoon, G., Dupré, N., Suchowersky, O., Bolduc, F.V., Parker, J.A., Dion, P.A., Drapeau, P., Rouleau, G.A., Bencheikh, B.O. :
Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia. American Journal of Human Genetics 98:1271, 2016. Pubmed reference: 27259058. DOI: 10.1016/j.ajhg.2016.05.009.
Wang, Y., Hersheson, J., Lopez, D., Hammer, M., Liu, Y., Lee, K.H., Pinto, V., Seinfeld, J., Wiethoff, S., Sun, J., Amouri, R., Hentati, F., Baudry, N., Tran, J., Singleton, A.B., Coutelier, M., Brice, A., Stevanin, G., Durr, A., Bi, X., Houlden, H., Baudry, M. :
Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. Cell Reports 16:79-91, 2016. Pubmed reference: 27320912. DOI: 10.1016/j.celrep.2016.05.044.
2014 Cherubini, G.B. :
Hereditary ataxia in Jack Russell terriers in the UK. Vet Rec 174:258, 2014. Pubmed reference: 24736826. DOI: 10.1136/vr.g1973.
Palmer, T. :
Hereditary ataxia in Jack Russell terriers in the UK. Vet Rec 174:258, 2014. Pubmed reference: 24736825. DOI: 10.1136/vr.g1972.
2013 Forman, O.P., De Risio, L., Mellersh, C.S. :
Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. PLoS One 8:e64627, 2013. Pubmed reference: 23741357. DOI: 10.1371/journal.pone.0064627.
2012 Simpson, K., Eminaga, S., Cherubini, G.B. :
Hereditary ataxia in Jack Russell terriers in the UK. Vet Rec 170:548, 2012. Pubmed reference: 22634896. DOI: 10.1136/vr.e3642.
Vanhaesebrouck, A., Franklin, R., Van Ham, L., Bhatti, S. :
Hereditary ataxia, myokymia and neuromyotonia in Jack Russell terriers. Vet Rec 171:131-2, 2012. Pubmed reference: 22872628. DOI: 10.1136/vr.e5021.
2004 Wessmann, A., Goedde, T., Fischer, A., Wohlsein, P., Hamann, H., Distl, O., Tipold, A. :
Hereditary ataxia in the Jack Russell Terrier--clinical and genetic investigations. J Vet Intern Med 18:515-21, 2004. Pubmed reference: 15320590.
1993 Moses, P.A. :
Cerebellar Ataxia in Jack Russell Terriers Veterinary Record 133:508, 1993.
1991 Cachin, M., Vandevelde, M. :
Congenital Tremor with Spongy Degeneration of the Central Nervous System in Two Puppies Journal of Veterinary Internal Medicine 5:87-90, 1991. Pubmed reference: 2061870.
1973 Hartley, W.J., Palmer, A.C. :
Ataxia in Jack Russell terriers. Acta Neuropathol 26:71-4, 1973. Pubmed reference: 4747697.

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