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.

A Homozygous RAB3GAP1:c.743delC Mutation in Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration

“…Histopathology revealed neuronal vacuolation and axonal neuropathy. 14 The occurrence of similar disease phenotypes associated with 2 different RAB3GAP1 mutations in 3 different breeds supports the existence of a causal relationship between the mutations and the disease.…”

“…The cause of an NVSD‐like disease phenotype in Boxers is currently unknown. A recent report describes POANV in Huskies with a SINE insert in RAB3GAP1 . Affected dogs had microphthalmia, miosis, cataracts, and persistent pupillary membranes.…”

“…44,45 Further investigation of membrane trafficking in dogs with In conclusion, our data support a causal relationship between homozygosity for the RAB3GAP1:c.743delC allele and NVSD in Rottweilers and POANV in BRT as well as the RAB3GAP1 SINE insertion and POANV in Huskies. 13, 14 We would recommend using POANV to describe all 3 diseases since it encompasses more of the signs associated with the mutations. The availability of DNA tests for the deletion allele should aid in the diagnosis of the disease and clarify the relationship between the various young onset neurologic diseases in Rottweilers.…”

“…13 A SINE insertion in RAB3GAP1 was also reported in Alaskan Huskies with POANV. 14 Similarities between the phenotypes of POANV and one of the previously reported diseases in young Rottweilers, neuronal vacuolation, and spinocerebellar degeneration (NVSD), 7 prompted us to determine if the same mutation is found in dogs with NVSD.…”

An analytical enrichment‐based review of structural genetic studies on keratoconus

“…35 They suggested SNP rs4954218, located next to the RAB3GAP1 gene, as a potential susceptibility locus for keratoconus. [37][38][39] In 2013, Lu et al 40 performed a meta-analysis on a large sample (>20 000) in European and Asian populations and identified 16 new loci associated with central corneal thickness conditions, including keratoconus and glaucoma, at genome-wide significance. 35 RAB3GAP1 gene encodes the catalytic subunit of a Rab GTPase activating protein, which mediates the hydrolysis of GTP-bound Rab3 to the GDP bound form.…”