The novel homozygous KCNJ10 c.986T&gt;C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

Poucke, Mario Van; Stee, Kimberley; Bhatti, Sofie; Vanhaesebrouck, An; Bosseler, Leslie; Peelman, Luc; Ham, Luc Van

doi:10.1038/ejhg.2016.157

Cited by 18 publications

(42 citation statements)

References 46 publications

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“…Terriers with spinocerebellar ataxia, generalised myokymia and neuromyotonia have been identified to have a missense mutation in KCNJ10 (Gilliam and others 2014), a gene that encodes for an inwardly rectifying potassium channel resulting in spinocerebellar ataxia with myokymia, seizures or both (SAMS). The same mutation has been found in Belgian malinois shepherd dogs with myokymia and neuromyotonia (Van Poucke and others 2017). However, not all terriers with SAMS are homozygous for the KCNJ10 mutation, suggesting that other mutations are likely responsible for this presentation.…”

Section: Twitchessupporting

confidence: 70%

Guide to tremor and twitch syndromes in dogs and cats

Lowrie¹

2021

In Practice

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Background: Tremors are relatively common in dogs and cats, with them representing a spectrum of disease from the benign through to life-threatening. Tremors associated with voluntary muscle contraction are divided into postural or kinetic. Twitches, or peripheral nerve hyperexcitability (PNH), are distinct to tremors, distinguished by their irregular rhythm, and have a range of outcomes. Twitches may manifest as fasciculations, myokymia, neuromyotonia, cramps, tetany or tetanus. Aim of the article: This article describes the common causes for twitches and tremors, and provides tips on how to differentiate them from one another, as well as how best to go about diagnosing and treating these conditions. Mark Lowrie qualified from the University of Cambridge in 2004. He is an RCVSrecognised and European Specialist in veterinary neurology, and has a master's degree on steroid responsive meningitisarteritis in dogs. He is currently clinical director at Dovecote Veterinary Hospital, Derby.

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Section: Twitchessupporting

confidence: 70%

Guide to tremor and twitch syndromes in dogs and cats

Lowrie¹

2021

In Practice

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“…This study revealed an unexpected genetic heterogeneity in clinically comparable cases, suggesting that more than one type of cerebellar ataxia is present in Belgian Shepherd dogs ( Kleiter et al 2011 ; Mauri et al 2017 ). The KCNJ10 variant was also identified in an independent study ( Stee et al 2016 ; Van Poucke et al 2017 ).…”

mentioning

confidence: 71%

A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

Mauri

Kleiter

Dietschi

et al. 2017

G3 Genes|Genomes|Genetics

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Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the ATP1B2 gene encoding the β2 subunit of the Na+/K+-ATPase holoenzyme (ATP1B2:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider ATP1B2:c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. ATP1B2 thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.

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“…In Belgian Shepherd dogs, a missense variant in KCNJ10 encoding a potassium channel causes spongy degeneration with cerebellar ataxia, subtype 1 (SDCA1, OMIA 002089–9615) [ 8 , 9 ]. The clinically similar SDCA2 in Belgian Shepherd dogs is due to a SINE insertion into ATP1B2 encoding the beta 2 subunit of the Na + /K + transporting ATPase (OMIA 002110–9615) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs

et al. 2021

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We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.

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The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

Cited by 18 publications

References 46 publications

Guide to tremor and twitch syndromes in dogs and cats

Guide to tremor and twitch syndromes in dogs and cats

A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs

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