title: The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.
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.
authors.affiliation: Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Mario
authors.initials: M
authors.lastname: Van Poucke
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stee
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Sofie F M
authors.initials: SF
authors.lastname: Bhatti
authors.affiliation: Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: An
authors.initials: A
authors.lastname: Vanhaesebrouck
authors.affiliation: Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bosseler
authors.affiliation: Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Peelman
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Ham
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004285:Dogs; D005260:Female; D005808:Genes, Recessive; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000662:veterinary; D006720:Homozygote; D008607:Intellectual Disability / Q000235:genetics* / Q000662:veterinary; D008297:Male; D020125:Mutation, Missense; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012640:Seizures / Q000235:genetics* / Q000662:veterinary; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying