A SINE Insertion in ATP1B2 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2).

Mauri, Nico; Kleiter, Miriam; Dietschi, Elisabeth; Leschnik, Michael; Högler, Sandra; Wiedmer, Michaela; Dietrich, Sara Joëlle; Henke, Diana; Steffen, Frank; Schuller, Simone; Gurtner, Corinne; Stokar von Neuforn, Nadine; O'Toole, Donal; Bilzer, Thomas; Herden, Christiane; Oevermann, Anna; Jagannathan, Vidhya; Leeb, Tosso (2017). A SINE Insertion in ATP1B2 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2). G3 Genes Genomes Genetics, 7(8), pp. 2729-2737. Genetics Society of America 10.1534/g3.117.043018

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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 a ~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 indicated a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knock-out 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 naturally occurring animal model for this disorder.

Item Type:

Journal Article (Original Article)

Division/Institute:

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 Veterinary Medicine (DKV) > Small Animal Clinic
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
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 Oct 2017 13:16

Last Modified:

30 Oct 2017 13:23

Publisher DOI:

10.1534/g3.117.043018

PubMed ID:

28620085

Uncontrolled Keywords:

Canis familiaris Malinois Na+/K+-ATPase adhesion molecule on glia β2 subunit

BORIS DOI:

10.7892/boris.101833

URI:

https://boris.unibe.ch/id/eprint/101833

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