Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 616907 (trait) , 114220 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0014827: autosomal recessive spastic paraplegia type 76

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200724), Parson Russell Terrier (Dog) (VBO_0200987).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: