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

Accepted version
Peer-reviewed

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Article

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Authors

Van Poucke, Mario 
Stee, Kimberley 
Bhatti, Sofie FM 
Bosseler, Leslie 

Abstract

SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.

Description

Keywords

Animals, Brain, Dogs, Female, Genes, Recessive, Hearing Loss, Sensorineural, Homozygote, Intellectual Disability, Male, Mutation, Missense, Potassium Channels, Inwardly Rectifying, Seizures

Journal Title

Eur J Hum Genet

Conference Name

Journal ISSN

1018-4813
1476-5438

Volume Title

25

Publisher

Nature

Rights

All rights reserved