A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).

Mauri, Nico; Kleiter, Miriam; Leschnik, Michael; Högler, Sandra; Dietschi, Elisabeth; Wiedmer, Michaela; Dietrich, Sara Joëlle; Henke, Diana; Steffen, Frank; Schuller, Simone; Gurtner, Corinne; Stokar-Regenscheit, Nadine; O'Toole, Donal; Bilzer, Thomas; Herden, Christiane; Oevermann, Anna; Jagannathan, Vidhya; Leeb, Tosso (2016). A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1). G3 Genes Genomes Genetics, 7(2), pp. 663-669. Genetics Society of America 10.1534/g3.116.038455

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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 the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10: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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Neurology
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > Small Animal Clinic > Small Animal Clinic, Internal Medicine
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Mauri, Nico; Dietschi, Elisabeth; Wiedmer, Michaela; Dietrich, Sara Joëlle; Henke, Diana; Schuller, Simone; Gurtner, Corinne; Stokar von Neuforn, Nadine; Oevermann, Anna; Jagannathan, Vidya and Leeb, Tosso

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

2160-1836

Publisher:

Genetics Society of America

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

30 Jan 2017 07:42

Last Modified:

10 Feb 2017 01:32

Publisher DOI:

10.1534/g3.116.038455

PubMed ID:

28007838

Uncontrolled Keywords:

Canis familiaris; EAST syndrome; Kir4.1; SeSAME syndrome; potassium channel

BORIS DOI:

10.7892/boris.93473

URI:

https://boris.unibe.ch/id/eprint/93473

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