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

Abstract

BackgroundA variety of presumed hereditary, neurologic diseases have been reported in young Rottweilers. Overlapping ages of onset and clinical signs have made antemortem diagnosis difficult. One of these diseases, neuronal vacuolation and spinocerebellar degeneration (NVSD) shares clinical and histological features with polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV), a recently described hereditary disease in Black Russian Terriers (BRTs). Dogs with POANV harbor mutations in RAB3GAP1 which codes for a protein involved in membrane trafficking.HypothesisRottweilers with NVSD will be homozygous for the RAB3GAP1:c.743delC allele associated with POANV in BRTs.AnimalsEight Rottweilers with NVSD confirmed at necropsy, 128 Rottweilers without early onset neurologic signs, and 468 randomly selected dogs from 169 other breeds.MethodsRetrospective case–control study. Dogs were genotyped for the RAB3GAP1:c.743delC allele with an allelic discrimination assay.ResultsAll 8 NVSD‐affected dogs were homozygous for the RAB3GAP1:c.743delC allele while the 128 NVSD‐free Rottweilers were either homozygous for the reference allele (n = 105) or heterozygous (n = 23) and the 468 genotyped dogs from other breeds were all homozygous for the reference allele.Conclusions and Clinical ImportanceThe RAB3GAP1:c.743delC mutation is associated with a similar phenotype in Rottweilers and BRTs. Identification of the mutation permits a DNA test that can aid in the diagnosis of NVSD and identify carriers of the trait so that breeders can avoid producing affected dogs. Disruption of membrane trafficking could explain the neuronal vacuolation seen in NVSD and other spongiform encephalopathies.

Juvenile‐onset polyneuropathy in American Staffordshire Terriers

“…The disease is very likely to be nonsyndromic in AST, whereas in the Rottweiler, Black Russian Terrier, and Boxer, PN with LP is a syndromic disease. In these breeds, affected dogs also exhibit ophthalmologic abnormalities such as microphthalmia, cataracts, miotic pupils, and persistent pupillary membranes . None of the dogs included in our study exhibited microphthalmia, miotic pupils, or persistant pupillary membranes although full ophthalmological examination was available only for 3 dogs.…”

“…Inherited PNs can either be syndromic, as part of a degenerative process involving the central and peripheral nervous system, or nonsyndromic, with clinical signs only related to PN . In the Black Russian Terrier, Rottweiler, and Boxer, the disease is syndromic with vacuolation in the neuronal cell bodies, axons and adrenal cells, and ocular abnormalities, similar to Warburg syndrome in humans . A causative mutation in the RAB3GAP1 gene has been identified in the Black Russian Terrier and Rottweiler .…”

“…In the Black Russian Terrier, Rottweiler, and Boxer, the disease is syndromic with vacuolation in the neuronal cell bodies, axons and adrenal cells, and ocular abnormalities, similar to Warburg syndrome in humans . A causative mutation in the RAB3GAP1 gene has been identified in the Black Russian Terrier and Rottweiler . In the other breeds, nonsyndromic forms lead to a disease similar to Charcot‐Marie‐Tooth (CMT) disease in humans, with axonal degeneration being a dominant finding .…”

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs

“…Although the specific diseases are often rare, and the genetic mutations can be breed-specific, hereditary ataxia is a key cause of movement disorders in dogs. Canine hereditary ataxia is typically inherited in an autosomal recessive manner, and disease-causing variants have been identified for some breeds [3][4][5][6][7][8][9][10][11][12]. Some of the genes implicated in canine ataxia had not previously been associated with disease in humans [12][13][14][15], whereas other forms of canine ataxia are caused by variants within the same genes that are associated with well characterised forms of human ataxia [4][5][6]16].…”

Neuronal vacuolation and spinocerebellar degeneration associated with altered neurotransmission

“…Moreover, in most disorders, the relationship between the appearance of a lesion and the underlying disease process is unclear [5]. Recently, a well-documented inherited disease of Rottweiler dogs named neuronal vacuolation spi-nocerebellar degeneration (NVSD) has been linked with the homozygosity for the RAB3GAP1:c.743delC allele [32]. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized predominantly by abnormalities of the nervous system including axonal peripheral neuropathy.…”