The whole genome sequences from a Rottweiler and Black Russian Terrier with overlapping neurological syndromes contain the same RAB3GAP1 frame shift mutation. T. Mhlanga-Mutangadura1, G. S. Johnson1, G. C. Johnson1, L. Hansen1, G. V. Tamassia1, J. F. Taylor2, R. D. Schnabel2, D. P. O'Brien1 1) College of Veterinary Medicine, University of Missouri, Columbia, MO; 2) College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO.
We generated whole-genome sequences (WGSs) with DNA from a 5-month-old male Rottweiler diagnosed with neuronal vacuolation and laryngeal paralysis and a 3-month-old female Black Russian Terrier diagnosed with juvenile laryngeal paralysis, polyneuropathy, microphthalmia, persistent pupillary membranes and cataracts. Initially we thought these two dogs had overlapping but distinct disease syndromes; however, both of their WGSs contained the same homozygous single base pair deletion: RAB3GAP1:c.743delC. The frame shift produced by this deletion predicts a premature stop codon and a truncated gene product RAB3GAP1:p.P248Lfs3* missing 730 C-terminal amino acids. In addition to the Rottweiler and Black Russian Terrier with the WGSs, the DNA samples from all 3 other affected Rottweilers and all 4 other Black Russian Terriers in our collection were homozygous for the c.743delC allele; whereas, 85 clinically normal Rottweilers and 41 clinically normal Black Russian Terriers tested either heterozygous (n = 18) or homozygous for the ancestral allele (n = 108). Truncating mutations in human RAB3GAP1 have been found in patients with Warburg micro syndrome. This severely debilitating developmental disorder is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, mental retardation, and hypogonadism. In contrast, Rab3gap1 knockout mice have exhibited only subtle abnormalities. The disease phenotype produced by the frame shift mutation in canine RAB3GAP1 appears to be less severe than that in the children with Warburg micro syndrome but much more severe than that of Rab3gap1 knockout mice. We are currently re-evaluating the disease phenotypes from affected dogs from the two breeds to see if they are, in fact, identical and to determine if they have other clinical signs in common with the Warburg micro syndrome patients.
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