A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1)

Wiedmer, Michaela; Oevermann, Anna; Borer, Stephanie; Gorgas, Daniela; Shelton, G. Diane; Drögemüller, Michaela; Jagannathan, Vidhya; Henke, Diana; Leeb, Tosso (2015). A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). G3 Genes Genomes Genetics, 6(2), pp. 255-262. Genetics Society of America 10.1534/g3.115.022707

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We observed a hereditary phenotype in Alaskan Huskies, which was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier and an unrelated control revealed a 218 bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1), which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1 deficient mice have a much milder phenotype than either humans or dogs. Thus the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the non-intentional breeding of affected dogs.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Radiology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)
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) > Experimental Clinical Research
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

UniBE Contributor:

Wiedmer, Michaela; Oevermann, Anna; Borer, Stephanie; Schweizer, Daniela Esther; Drögemüller, Michaela; Jagannathan, Vidya; Henke, Diana and Leeb, Tosso

Subjects:

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

ISSN:

2160-1836

Publisher:

Genetics Society of America

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

08 Dec 2015 08:09

Last Modified:

03 Nov 2017 16:35

Publisher DOI:

10.1534/g3.115.022707

PubMed ID:

26596647

Uncontrolled Keywords:

animal model canis familiaris dog linkage whole genome sequencing

BORIS DOI:

10.7892/boris.73434

URI:

https://boris.unibe.ch/id/eprint/73434

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