title: A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1).
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.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wiedmer
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
authors.affiliation: Ophthalmology Service, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Borer-Germann
authors.affiliation: Division of Clinical Radiology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gorgas
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Henke
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland tosso.leeb@vetsuisse.unibe.ch.
authors.forename: Tosso
authors.identifier: http://orcid.org/0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000818:Animals; D001947:Breeding; D002386:Cataract / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D002874:Chromosome Mapping; D003315:Cornea / Q000002:abnormalities*; D004285:Dogs; D005091:Exons; D056726:Genetic Association Studies; D008040:Genetic Linkage; D016678:Genome; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis* / Q000235:genetics*; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics*; D016254:Mutagenesis, Insertional; D009896:Optic Atrophy / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic; D020692:rab3 GTP-Binding Proteins / Q000235:genetics*
chemical_list: D020692:rab3 GTP-Binding Proteins
keywords: animal model; canis familiaris; dog; homozygosity; linkage; whole genome sequencing