The distributions of two SOD1 missense mutations in the pet dog population and their association with canine degenerative myelopathy, a model for amyotrophic lateral sclerosis. R. Zeng1, J. R. Coates2, L. Hansen1, G. C. Johnson1, F. A. Wininger2, M. L. Katz3, G. S. Johnson1 1) Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA; 2) 2Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA; 3) Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA.
Canine Degenerative Myelopathy (DM) is a naturally occurring, progressive, adult-onset neurodegenerative disease and a potential large animal model for amyotrophic lateral sclerosis. The initial signs of DM include asymmetric general proprioceptive ataxia and spastic paresis in the pelvic limbs. Over a period of 9 to 12 months, affected dogs become nonambulatory paraplegic with proprioceptive deficits followed by lower motor neuron signs. Owners usually elect euthanasia at this stage. If euthanasia is delayed, clinical signs progress to flaccid tetraplegia and widespread muscle atrophy and may involve the brain stem with signs of dysphagia. Previously, we reported an association between DM and homozygosity for a c.118G>A missense mutation in the canine ortholog of SOD1 in five dog breeds. In addition, we have reported a case of DM in a single Bernese Mountain Dog that was homozygous for a SOD1:c.52G>T missense mutation. For the current report we used TaqMan allelic discrimination assays to estimate the breed-specific distributions of the SOD1:c.118A and SOD1:c.52T alleles in the canine pet populations. So far we have genotyped 26,898 dogs at SOD1:c.118G>A and 1,577 dogs at SOD1:c.52A>T. Representatives from 217 different dog breeds were genotyped at SOD1:c.118G>A and 115 of them were found to segregate the SOD1:c.118A allele. The Wire Fox Terrier breed had the highest SOD1:c.118A allele frequency: 0.94. Of the 60 breeds examined at SOD1:c.52A>T, the SOD1:c.52T allele was only found in members of the Bernese Mountain Dog breed, in which the allele frequency among the 884 genotyped breed members genotyped by us was 0.032. Only 2 Bernese Mountain Dogs were homozygous for the SOD1:c.52T allele: one has been euthanized because of DM, the other one is currently too young to develop signs. We also identified 24 Bernese Mountain Dogs that were SOD1:c.52A,c.118A/c.52T,c.118G compound heterozygotes. Pertinent clinical information was available for 6 of the 9 compound heterozygotes over 8 years of age. Four of the compound heterozygous Bernese Mountain Dog have developed clinical signs suggestive of DM; the other two died from unrelated diseases before their tenth birthday. In addition, we have examined 6 dogs from four different breeds that had histopathologically confirmed DM and were A/G heterozygotes at SOD1:c.118, but had no other SOD1 sequence variants. Finally, one German Shepherd Dog without any SOD1 sequence variants had histopathologically confirmed DM.
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