Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs

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dc.contributor University of Helsinki, Department of Medical and Clinical Genetics en
dc.contributor University of Helsinki, Helsinki One Health (HOH) en Jenkins, Christopher A. Kalmar, Lajos Matiasek, Kaspar Mari, Lorenzo Kyöstilä, Kaisa Lohi, Hannes Schofield, Ellen C. Mellersh, Cathryn S. De Risio, Luisa Ricketts, Sally L. 2020-03-12T14:25:01Z 2020-03-12T14:25:01Z 2020-01-30
dc.identifier.citation 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 2020 , ' Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs ' , PLoS Genetics , vol. 16 , no. 1 , 1008527 . en
dc.identifier.issn 1553-7390
dc.identifier.other PURE: 132187878
dc.identifier.other PURE UUID: 9d7053be-ec9f-4949-a568-c0958e59eff7
dc.identifier.other RIS: urn:F51E15B9CEFC913CFA4F2125B6E57284
dc.identifier.other WOS: 000514903300020
dc.description.abstract Author summary Hereditary ataxias, which are a group of disorders characterised by incoordination of movement, are typically incurable and there are often no disease-modifying treatments available. Canine hereditary ataxias are a notable group of movement disorders in dogs, and represent well characterised naturally occurring disease models of ataxia that can help improve our understanding of the underlying biology of the disorder in both dogs and humans. We used the whole genome sequences of two affected siblings to investigate the genetic cause of a slowly progressive form of hereditary ataxia in the Norwegian Buhund dog breed, and identified a single base change within the KCNIP4 gene. We have characterised the expression of KCNIP4 in the dog, and investigated the effect of the identified mutation. This gene has not previously been implicated in inherited ataxia in any species, and our findings suggest that this and related genes represent potential candidates for ataxia in future studies in other species. Our findings will allow dog breeders to avoid producing affected dogs, reduce the disease allele frequency, and eventually eliminate the disease from the breed, through the use of a DNA test. A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), 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. en
dc.format.extent 20
dc.language.iso eng
dc.relation.ispartof PLoS Genetics
dc.rights en
dc.subject CLONING en
dc.subject KCNJ10 en
dc.subject MUTATIONS en
dc.subject 1184 Genetics, developmental biology, physiology en
dc.subject 413 Veterinary science en
dc.title Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs en
dc.type Article
dc.description.version Peer reviewed
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion

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