OMIA:001820-9615 : Ataxia, spinocerebellar, CAPN1-related in Canis lupus familiaris
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 616907 (trait) , 114220 (gene)
Links to MONDO diseases:
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.
History: It is important to note that the discovery of a likely causal variant for this disorder in dogs (documented below) by Forman et al. (2013) led to the discovery of likely causal variants for the homologous disorder in humans, Danio rerio (zebrafish), Drosophila melanogaster and Caenorhabditis elegans by Gan-Or et al. (2016), and in humans and mice by Wang et al. (2016).
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.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|CAPN1||calpain 1, (mu/I) large subunit||Canis lupus familiaris||18||NC_051822.1 (53053236..53024769)||CAPN1||Homologene, Ensembl , NCBI gene|
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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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|105||Parson Russell Terrier||Ataxia, spinocerebellar||CAPN1||missense||Naturally occurring variant||CanFam3.1||18||g.52009339C>T||c.344G>A||p.(C115Y)||XM_540866.5; XP_540866.2||2013||23741357||Genomic coordinates in CanFam3.1 provided by Robert Kuhn|
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.
|2019||Lewis, T.W., Mellersh, C.S. :|
|Changes in mutation frequency of eight Mendelian inherited disorders in eight pedigree dog populations following introduction of a commercial DNA test. PLoS One 14:e0209864, 2019. Pubmed reference: 30650096 . DOI: 10.1371/journal.pone.0209864.|
|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. :|
|[Correction to] 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.|
|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., Ouled Amar Bencheikh, B. :|
|Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia. Am J Hum Genet 98:1038-1046, 2016. Pubmed reference: 27153400 . DOI: 10.1016/j.ajhg.2016.04.002.|
|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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