Tags

Type your tag names separated by a space and hit enter

A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1).
G3 (Bethesda). 2015 Nov 23; 6(2):255-62.G

Abstract

We observed a hereditary phenotype in Alaskan Huskies that 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 nonintentional breeding of affected dogs.

Authors+Show Affiliations

Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Ophthalmology Service, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Division of Clinical Radiology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California 92093.Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland tosso.leeb@vetsuisse.unibe.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26596647

Citation

Wiedmer, Michaela, et al. "A RAB3GAP1 SINE Insertion in Alaskan Huskies With Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1)." G3 (Bethesda, Md.), vol. 6, no. 2, 2015, pp. 255-62.
Wiedmer M, Oevermann A, Borer-Germann SE, et al. A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). G3 (Bethesda). 2015;6(2):255-62.
Wiedmer, M., Oevermann, A., Borer-Germann, S. E., Gorgas, D., Shelton, G. D., Drögemüller, M., Jagannathan, V., Henke, D., & Leeb, T. (2015). A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). G3 (Bethesda, Md.), 6(2), 255-62. https://doi.org/10.1534/g3.115.022707
Wiedmer M, et al. A RAB3GAP1 SINE Insertion in Alaskan Huskies With Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). G3 (Bethesda). 2015 Nov 23;6(2):255-62. PubMed PMID: 26596647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). AU - Wiedmer,Michaela, AU - Oevermann,Anna, AU - Borer-Germann,Stephanie E, AU - Gorgas,Daniela, AU - Shelton,G Diane, AU - Drögemüller,Michaela, AU - Jagannathan,Vidhya, AU - Henke,Diana, AU - Leeb,Tosso, Y1 - 2015/11/23/ PY - 2015/11/25/entrez PY - 2015/11/26/pubmed PY - 2016/10/21/medline KW - animal model KW - canis familiaris KW - dog KW - homozygosity KW - linkage KW - whole genome sequencing SP - 255 EP - 62 JF - G3 (Bethesda, Md.) JO - G3 (Bethesda) VL - 6 IS - 2 N2 - We observed a hereditary phenotype in Alaskan Huskies that 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 nonintentional breeding of affected dogs. SN - 2160-1836 UR - https://www.unboundmedicine.com/medline/citation/26596647/A_RAB3GAP1_SINE_Insertion_in_Alaskan_Huskies_with_Polyneuropathy_Ocular_Abnormalities_and_Neuronal_Vacuolation__POANV__Resembling_Human_Warburg_Micro_Syndrome_1__WARBM1__ L2 - http://www.g3journal.org/cgi/pmidlookup?view=long&pmid=26596647 DB - PRIME DP - Unbound Medicine ER -