Categories: Nervous system phene

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

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific name: Progressive cerebellar ataxia

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."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Affected Norwegian Buhunds generally present as puppies with slowly progressing abnormalities in gait and balance. There is generally no irregularity of behaviour or demeanour, however they have a broad-based stance and hypermetria in all limbs, truncal ataxia and persistent head tremors (Mari et al., 2018). A bilaterally reduced menace response may be present, however no other abnormalities are likely on physical exam, CBC or serum biochemistry, and no abnormalities have been noted on MRI imaging or CSF sampling in known cases (Mari et al., 2018). IT thanks DVM student Teresa McIntyre, who provided the basis of this contribution in May 2023.

Pathology: Histopathology will find mild evidence of neuronal degeneration and reduced Purkinje fibre differentiation in regions of the cerebellum (Mari et al., 2018). IT thanks DVM student Teresa McIntyre, who provided the basis of this contribution in May 2023.

Breed: Norwegian Buhund (Dog) (VBO_0200953).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: