OMIA 002089-9615 : Ataxia, cerebellar, KCNJ10-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 612780

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Spinocerebellar ataxia with myokymia, seizures or both (SAMS); spongy degeneration with cerebellar ataxia 1 (SDCA1)

Species-specific description: Ataxia is characterized by uncoordinated movements and represents a relatively non-specific clinical sign. This entry describes ataxia forms that are caused by genetic variants in the KCNJ10 gene. A phenotypically closely related ataxia in Russell group terriers is caused by a variant in the CAPN1 gene. A phenotypically closely related ataxia in Belgian Shepherds is caused by a variant in the ATP1B2 gene. Other phenotypically related ataxias in dogs may also be caused by variants in the GRM1, ITPR1, RAB24, SEL1L, SNX14, and SPTBN2 genes. There are currently 2 different KCNJ10 pathogenic variants known in dogs (p.Ile209Met in various Terrier breeds and p.Leu329Pro in Belgian Shephers). These canine disorders represent models for SeSAME/EAST syndrome in humans (see MIM link above).

Mapping: Mauri et al. (2017) investigated six litters of Malinois dogs with ataxic puppies by linkage analysis. This analysis revealed heterogeneity in the material. Four of the six litters had overlapping linkage signals. The authors additionally performed a homozygosity mapping analysis, for which they used six affected puppies from the four families and one additional unrelated case. The combined linkage and homozygosity analysis resulted in a ~1.4 Mb critical interval on chromosome 38 (chr38:21,060,597-22,475,242; CanFam 3.1 assembly).

Molecular basis: By whole-genome sequencing a single SAMS affected Russell group terrier (RGT) dog, and comparing that sequence with whole-genome sequence from 81 canid reference genomes, Gilliam et al. (2014) identified 23 missense variants that were homozygous in the affected dog. Of the two variants that occurred in comparative candidate genes, one (KCNJ10:c.627C>G; p.Ile209Met) was shown by subsequent sequencing and genotyping of other dogs to be causal for this subtype of ataxia, namely "spinocerebellar ataxia with myokymia, seizures, or both (SAMS)". Rohdin et al (2015) confirmed these findings and noted that the KCNJ10:c.627C>G (p.Ile209Met) variant also segregates in Smooth-Haired Fox Terriers and related breeds. Gast et al. (2016) confirmed that the KCNJ10 c.627C>G (p.Ile209Met) variant accounts for most (but not all) cases in another cohort of Parson Russell Terriers and in Jack Russell Terriers.

A likely causal variant in Malinois dogs with spongy degeneration with cerebellar ataxia 1 (SDCA1), namely a missense mutation in KCNJ10: c.986T>C; p.Leu329Pro, was reported by a Belgian/UK team (Stee et al., 2016; Van Poucke et al., 2017, accepted for publication 29 September 2016). The phenotype in SDCA1 affected Malinois dogs is slightly different from the phenotype in the terriers with SAMS. Mauri et al. (2017; accepted for publication 16 December 2016) reported the same likely causal mutation in this breed.

Clinical features: Spinocerebellar ataxia with myokymia, seizures, or both (SAMS): "The median age at onset of cerebellar ataxia in 12 dogs was 3 months (range, 2–6 months)" (Gilliam et al. 2014). Ten out of twelve SAMS-affected dogs of the Russell terrier group showed muscle twitches (myokymia). The median age at onset for myokymia was 6 months (range, 3–8 months). Some SAMS dogs developed seizures. (Gilliam et al. 2014).

Spongy degeneration with cerebellar ataxia 1 (SDCA1): This phenotype occurs in Malinois dogs and has an earlier age of onset than SAMS. Kleiter et al. (2011) investigated 5 closely related litters with presumed SDCA1 (the KCNJ10:p.Leu329Pro variant was confirmed in only one of the litters, Mauri et al. 2017). Malinois puppies with SDCA1 developed a severe ataxia at 4-7 weeks of age. Affected dogs showed shivering and were unable to start walking without falling. The severe condition resulted in euthanasia at 5-13 weeks of age (Kleiter et al. 2011).

Van Poucke et al. (2017) reported another detailed clinical analysis of 3 SDCA1 affected Malinois dogs. One of the dogs was still alive at 1 year of age despite severely debilitating non-ambulatory ataxia. Van Poucke et al. noted ataxia, myokymia and neuromyotonia as well as auditory changes in SDCA1 affected dogs.

Pathology: Macroscopically the central nervous system (CNS) and peripheral nervous system (PNS) of dogs carrying the KCNJ10 variants are normal. Based on histopathology, there is apparently some phenotypical variation depending on the breed and report. In Parson Russell Terriers and in Jack Russell Terriers the KCNJ10 c.627C>G (p.Ile209Met) variant is associated with bilateral-symmetrical axonal degeneration in the ventral and lateral funiculi of the spinal cord (Gilliam et al. 2014). Van Poucke et al. (2017) describe a similar axonal degeneration in the ventral funiculi and in the brainstem and cerebellum of Malinois dogs with the KCNJ10: c.986T>C (p.Leu329Pro) variant in association with myelin vacuolisation and additionally axonal changes in the PNS. In comparison, in the descriptions by Kleiter et al. (2011) and Mauri et al. (2017) the neuropathology of affected Malinois dogs is dominated by vacuolisation (spongy degeneration) targeting the cerebellar nuclei, granule cell layer and cerebellar white matter. This vacuolisation is accompanied by axonal degeneration in the brain and spinal cord, which is mainly characterized by the presence of axonal swellings.

Breeds: Smooth-Haired Fox Terrier, Belgian Shepherd, Jack Russell Terrier, Malinois, Parson Russell Terrier, Russell Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
KCNJ10 potassium channel, inwardly rectifying subfamily J, member 10 Canis lupus familiaris 38 NC_006620.3 (22114718..22143625) KCNJ10 Homologene, Ensembl, NCBI gene

Variants

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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
Smooth-Haired Fox Terrier Jack Russell Terrier Parson Russell Terrier Ataxia, cerebellar, KCNJ10-related KCNJ10 missense c.627C>G p.Ile209Met 2014 24708069
Malinois Spongy degeneration with cerebellar ataxia 1 (SDCA1) KCNJ10 missense c.986T>C p.Leu329Pro 2017 27966545 28007838
Jack Russell Terrier Ataxia, cerebellar, KCNJ10-related KCNJ10 insertion, small (<=20) g.22141027insC 2016 27724896

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.
2017 Bockenhauer, D., Kleta, R. :
Of dogs and men. Eur J Hum Genet. 25:161 only, 2017. Pubmed reference: 28079058. DOI: 10.1038/ejhg.2016.161.
Mauri, N., Kleiter, M., Leschnik, M., Högler, S., Dietschi, E., Wiedmer, M., Dietrich, J., Henke, D., Steffen, F., Schuller, S., Gurtner, C., Stokar-Regenscheit, N., O'Toole, D., Bilzer, T., Herden, C., Oevermann, A., Jagannathan, V., Leeb, T. :
A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1). G3 (Bethesda) 7:663-669, 2017. Pubmed reference: 28007838. DOI: 10.1534/g3.116.038455.
Van Poucke, M., Stee, K., Bhatti, S.F., Vanhaesebrouck, A., Bosseler, L., Peelman, L.J., Van Ham, L. :
The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs Eur J Hum Genet. 25:222-226, 2017. Pubmed reference: 27966545. DOI: 10.1038/ejhg.2016.157.
2016 Gast, A.C., Metzger, J., Tipold, A., Distl, O. :
Genome-wide association study for hereditary ataxia in the Parson Russell Terrier and DNA-testing for ataxia-associated mutations in the Parson and Jack Russell Terrier. BMC Vet Res 12:225, 2016. Pubmed reference: 27724896. DOI: 10.1186/s12917-016-0862-x.
Stee, K., Van Poucke, M., Bhatti, S., Vanhaesebrouck, A., Bosseler, L., Peelman, L., Van Ham, L. :
The novel homozygous KCNJ10 c.986T>C (p.Leu329-Pro) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs (conference abstract) Journal of Veterinary Internal Medicine (Proceedings 29th Symposium ESVN-ECVN Edinburgh, United Kingdom 16th–17th September 2016) 30:1934 only, 2016.
2015 Rohdin, C., Gilliam, D., O'Leary, C.A., O'Brien, D.P., Coates, J.R., Johnson, G.S., Jäderlund, K.H. :
A KCNJ10 mutation previously identified in the Russell group of terriers also occurs in Smooth-Haired Fox Terriers with hereditary ataxia and in related breeds. Acta Vet Scand 57:26, 2015. Pubmed reference: 25998802. DOI: 10.1186/s13028-015-0115-1.
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.
Gilliam, D., O'Brien, D.P., Coates, J.R., Johnson, G.S., Johnson, G.C., Mhlanga-Mutangadura, T., Hansen, L., Taylor, J.F., Schnabel, R.D. :
A homozygous KCNJ10 mutation in Jack Russell Terriers and related breeds with spinocerebellar ataxia with myokymia, seizures, or both. J Vet Intern Med 28:871-7, 2014. Pubmed reference: 24708069. DOI: 10.1111/jvim.12355.
Palmer, T. :
Hereditary ataxia in Jack Russell terriers in the UK. Vet Rec 174:258, 2014. Pubmed reference: 24736825. DOI: 10.1136/vr.g1972.
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.
2011 Kleiter, M., Högler, S., Kneissl, S., Url, A., Leschnik, M. :
Spongy degeneration with cerebellar ataxia in Malinois puppies: a hereditary autosomal recessive disorder? J Vet Intern Med 25:490-6, 2011. Pubmed reference: 21488963. DOI: 10.1111/j.1939-1676.2011.0720.x.
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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