OMIA 002240-9615 : Ataxia, cerebellar, KCNIP4-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 608182

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Molecular basis: By whole-genome sequencing two affected Norwegian Buhund sibs, comparing these sequences against 405 whole-genome sequences from other breeds, and then extensively genotyping the most likely variant, Jenkins et al. (2020) identified the most likely causal variant as "a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), [that] is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in voltage-gated potassium channel function in the cerebellum and should be investigated as potential candidate genes for cerebellar ataxia in future studies in other species."

Breed: Norwegian buhund.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
KCNIP4 Kv channel interacting protein 4 Canis lupus familiaris 3 NC_006585.3 (88013222..88896093) KCNIP4 Homologene, Ensembl, NCBI gene

Variants

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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.

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
Norwegian buhund Ataxia, cerebellar, KCNIP4-related KCNIP4 missense CanFam3.1 3 g.88,890,674T>C p.(Trp?Arg) NC_006585.3:g.88890674T>C (Jenkins et al., 2020) 2020 31999692

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.
2020 Jenkins, C.A., Kalmar, L., Matiasek, K., Mari, L., Kyöstilä, K., Lohi, H., Schofield, E.C., Mellersh, C.S., De Risio, L., Ricketts, S.L. :
Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs. PLoS Genet 16:e1008527, 2020. Pubmed reference: 31999692. DOI: 10.1371/journal.pgen.1008527.
2018 Mari, L., Matiasek, K., Jenkins, C.A., De Stefani, A., Ricketts, S.L., Forman, O., De Risio, L. :
Hereditary ataxia in four related Norwegian Buhunds. J Am Vet Med Assoc 253:774-780, 2018. Pubmed reference: 30179085. DOI: 10.2460/javma.253.6.774.

Edit History


  • Created by Frank Nicholas on 03 Feb 2020
  • Changed by Frank Nicholas on 03 Feb 2020