title: A Missense Variant inKCNJ10in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).
abstract: Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in theKCNJ10gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants inKCNJ10were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we considerKCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights 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. These dogs represent an animal model for the human EAST syndrome.
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Nico
authors.identifier: 0000-0001-8980-4053
authors.initials: N
authors.lastname: Mauri
authors.affiliation: University Clinic for Small Animals, Department for Companion Animals and Horses.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kleiter
authors.affiliation: University Clinic for Small Animals, Department for Companion Animals and Horses.
authors.forename: Michael
authors.initials: M
authors.lastname: Leschnik
authors.affiliation: Institute of Pathology and Forensic Medicine, Department of Pathobiology, University of Veterinary Medicine Vienna, 1210, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Högler
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dietschi
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wiedmer
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Division of Clinical Neurology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Henke
authors.affiliation: Section of Neurology, Department of Small Animals, Vetsuisse Faculty, University of Zurich, 8057, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Steffen
authors.affiliation: Division of Small Animal Internal Medicine, Department of Clinical Veterinary Medicine.
authors.forename: Simone
authors.initials: S
authors.lastname: Schuller
authors.affiliation: Institute of Animal Pathology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gurtner
authors.affiliation: Institute of Animal Pathology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Stokar-Regenscheit
authors.affiliation: Wyoming State Veterinary Laboratory, University of Wyoming, Laramie, Wyoming 82070.
authors.forename: Donal
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: Institute of Neuropathology, University Hospital Düsseldorf, 40225, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bilzer
authors.affiliation: Institute of Veterinary Pathology, Justus-Liebig-University, 35392 Gießen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Herden
authors.affiliation: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health.
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Genetics, and Vetsuisse Faculty, University of Bern, 3001, Switzerland tosso.leeb@vetsuisse.unibe.ch.
authors.forename: Tosso
authors.identifier: 0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D001947:Breeding; D017825:Canavan Disease / Q000235:genetics* / Q000503:physiopathology / Q000662:veterinary; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology / Q000662:veterinary; D004285:Dogs; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying
keywords: Canis familiaris; EAST syndrome; Kir4.1; Malinois; SeSAME syndrome; animal model; brain; central nervous system; neurology; potassium channel