OMIA 001970-9615 : Polyneuropathy, RAB3GAP1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 600118

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Polyneuropathy, ocular abnormalities and neuronal vacuolation

Species-specific symbol: POANV

History: A phenotype of neuronal vacuolation and spinocerebellar degeneration was initially discovered in Rottweiler dogs (Kortz et al. 1997; Andrade-Neto et al. 1998; de Lahunta and Summers, 1998; Eger et al. 1998; Vandeningh et al. 1998; Pumarola et al. 1999). Similar neurodegenerative phenotypes in combination with microphthalmia were also reported in Black Russian Terriers and Alaskan Huskies (Granger, 2011; Wiedmer et al. 2015).

Mapping: Wiedmer et al. (2015) performed linkage mapping with illumina SNP chip genotypes in a cohort of 18 Alaskan Huskies and obtained maximum LOD scores of 1.976 for five different genome segments on chromosomes 2, 11, 15, 17, and 19. The further performed homozygosity mapping in four affected Alaskan Huskies and found a single homozygous region with shared haplotypes amongt the 4 cases on chromosome 19. The combined linkage and homozygosity analysis thus defined an exact critical interval of 4,086,630 bp at chr19:36,483,638–40,570,267 (CanFam 3.1 assembly).

Molecular basis: Wiedmer et al. (2015) performed whole genome sequencing of a POANV affected Alaskan Husky. An initial automated small-scale variant analysis of the sequence data did not reveal a plausible candidate variant. Wiedmer et al. then visually inspected the short read alignments of the affected Alaskan Husky in the critical interval on chromosome 19 and identified a 218 bp SINE insertion into exon 7 of the RAB3GAP1 gene, (RAB3GAP1:c.614_615insLN864704:g.123_340). The SINE insertion was perfectly associated with the POANV phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of 68 other breeds. Wiedmer et al. (2015) observed that the SINE insertion leads to aberrant splicing. The mutant allele predominantly gives rise to a transcript that uses an internal splice acceptor within the SINE insertion. This mutant transcript is predicted to encode a protein, in which 39 wildtype amino acids are replaced by 46 mutant amino acids. A minor amount of transcript, in which the entire exon 7 was skipped, was observed in RNA from blood cells, but not in brain.

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

Variants

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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

References


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.

Edit History


  • Created by Tosso Leeb on 03 Dec 2015
  • Changed by Tosso Leeb on 03 Dec 2015
  • Changed by Tosso Leeb on 11 Dec 2015
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