OMIA 001970-9615 : Polyneuropathy, RAB3GAP1-related in Canis lupus familiaris
Mhlanga-Mutangadura et al. (2016) performed whole genome sequencing at 29.3x coverage of a POANV affected Black Russian Terrier. They compared the sequence data to the genomes of 73 control dogs and identified 71 private homozygous variants in the POANV affected dog, which were predicted to alter the amino acid of a gene product. Based on a literature-based survey of the affected genes, a single base deletion in the RAB3GAP1 gene was identified as the most likely causative variant (RAB3GAP1:c.743delC). This variant was perfectly associated with the POANV phenotype in a cohort of 262 Black Russian Terriers. The variant was absent from 100 randomly selected dogs of other breeds.Clinical features: In Alaskan Huskies neurological signs start at 4 to 5 months of age with visual problems. Slightly later affected dogs display an altered voice due to laryngeal paralysis, regurgitation, and gait abnormalities progressing to a severe ataxia. Dogs are typically euthanized between 8 and 16 months of age. Affected dogs have bilateral microphthalmia, small pupils, and lenses with cataract. Some affected dogs additionally exhibit strabismus and/or persistent pupillary membranes (Wiedmer et al. 2015).
The Black Russian Terriers presented slightly earlier than the Alaskan Huskies at 3 months of age with laryngeal paralysis and respiratory distress. They were all euthanized by 6 months of age for severe dyspnea (Mhlanga-Mutangadura et al. 2016 and Dennis O'Brien, personal communication).Pathology: Neuropathological examinations in affected Alaskan Huskies showed bilaterally symmetrical chronic Wallerian-type axonal degeneration in the spinal cord, which was characterized by dilated myelin sheaths containing either axonal spheroids and fragments or myelinophages. Lesions were most prominent in the superficial dorsolateral white matter tracts of the cervical and thoracic segments, where they consisted of areas of axonal and myelin loss replaced by gliotic tissue. Additionally, widely spread, bilateral-symmetrical, subtle to severe neuronal vacuolation was present in the spinal cord grey matter, facial nucleus, gracile and cuneate nuclei, vestibular nuclei, cerebellar nuclei, oculomotor nuclei, substantia nigra, thalamic nuclei, hypothalamus, hippocampus and cortex. The vacuolation was characterized by the presence of one to multiple clearly defined vacuoles of varying size in the neuronal somata and was prominent in the cerebellar nuclei. Vacuoles were also observed in the surrounding neuropil, which contained scattered axonal spheroids and was gliotic. In the cerebellar cortex, mild to severe Purkinje cell degeneration and loss were observed, associated with cerebellar atrophy in one case. Scattered axonal spheroids were present in the granule cell layer. Mild vacuolation and scattered fragmented axons were observed in the white matter of the cerebellum and brainstem. Pathological prion protein deposition was absent.
In muscle and peripheral nerve biopsies from affected Alaskan Huskies, a mild variability in myofiber size with scattered atrophic fibers having an angular to anguloid shape and of both fiber types was observed. Multifocal areas of type 1 fiber grouping were observed in one of three investigated dogs. Intramuscular nerve branches were mildly to moderately depleted of myelinated fibers. Large fiber loss was evident in the peroneal and vagus nerves resulting from axonal degeneration in two of three investigated dogs. Regenerative changes were not obvious, and the vagosympathetic nerve did not reveal any specific abnormalities (Wiedmer et al. 2015).
The pathological alterations in POANV affected Black Russian Terriers were similar to those seen in Alaskan Huskies. Mhlanga-Mutangadura et al. 2015 additionally found vacuoles within axons in the peripheral nerves. In electron microscopy, Mhlanga-Mutangadura et al. 2015 showed that the vacuoles were membrane bound and contained scant fibrillary debris and occasional an electron dense core of material. They did not stain with oil red O which ruled out lipid droplets. In the Purkinje cells, there were numerous small vacuoles.Breeds: Alaskan Husky, Black Russian Terrier, Rottweiler. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|RAB3GAP1||RAB3 GTPase activating protein subunit 1 (catalytic)||Canis lupus familiaris||19||NC_006601.3 (37861844..38006433)||RAB3GAP1||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Alaskan Husky||Polyneuropathy, ocular abnormalities and neuronal vacuolation||RAB3GAP1||insertion, gross (>20)||a 218 bp SINE insertion into exon 7 of the RAB3GAP1 gene (RAB3GAP1:c.614_615insLN864704:g.123_340)||2015||26596647|
|Black Russian Terrier||Polyneuropathy, ocular abnormalities and neuronal vacuolation||RAB3GAP1||deletion, small (<=20)||c.743delC||2016||26607784|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2016||Mhlanga-Mutangadura, T., Johnson, G.S., Schnabel, R.D., Taylor, J.F., Johnson, G.C., Katz, M.L., Shelton, G.D., Lever, T.E., Giuliano, E., Granger, N., Shomper, J., O'Brien, D.P. :|
|A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs. Neurobiol Dis 86:75-85, 2016. Pubmed reference: 26607784. DOI: 10.1016/j.nbd.2015.11.016.|
|2015||Wiedmer, M., Oevermann, A., Borer-Germann, S.E., Gorgas, D., Shelton, G.D., Drögemüller, M., Jagannathan, V., Henke, D., Leeb, T. :|
|A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). G3 (Bethesda) 6:255-62, 2015. Pubmed reference: 26596647. DOI: 10.1534/g3.115.022707.|
|2011||Granger, N. :|
|Canine inherited motor and sensory neuropathies: an updated classification in 22 breeds and comparison to Charcot-Marie-Tooth disease. Vet J 188:274-85, 2011. Pubmed reference: 20638305. DOI: 10.1016/j.tvjl.2010.06.003.|
|1999||Pumarola, M., Fondevila, D., Borrás, D., Majó, N., Ferrer, I. :|
|Neuronal vacuolation in young Rottweiler dogs. Acta Neuropathol 97:192-5, 1999. Pubmed reference: 9928831.|
|1998||Andradeneto, J.P., Jardim, L.S., Alessi, A.C. :|
|Neuronal vacuolation in young Rottweilers Veterinary Record 143:116, 1998.|
|Eger, C.E., Huxtable, C.R., Chester, Z.C., Summers, B.A. :|
|Progressive tetraparesis and laryngeal paralysis in a young rottweiler with neuronal vacuolation and axonal degeneration: an Australian case. Aust Vet J 76:733-7, 1998. Pubmed reference: 9862062.|
|Vandeningh, T.S.G.A.M., Mandigers, P.J.J., Vannes, J.J. :|
|A neuronal vacuolar disorder in young rottweiler dogs Veterinary Record 142:245-247, 1998. Pubmed reference: 9549867.|
|de Lahunta, A., Summers, B.A. :|
|The laryngeal lesion in young dogs with neuronal vacuolation and spinocerebellar degeneration. Vet Pathol 35:316-7, 1998. Pubmed reference: 9684979.|
|1997||Kortz, G.D., Meier, W.A., Higgins, R.J., French, R.A., Mckiernan, B.C., Fatzer, R., Zachary, J.F. :|
|Neuronal vacuolation and spinocerebellar degeneration in young rottweiler dogs Veterinary Pathology 34:296-302, 1997. Pubmed reference: 9240838.|
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