Breed Distribution of SOD1 Alleles Previously Associated with Canine Degenerative Myelopathy

Abstract

BackgroundPrevious reports associated 2 mutant SOD1 alleles (SOD1:c.118A and SOD1:c.52T) with degenerative myelopathy in 6 canine breeds. The distribution of these alleles in other breeds has not been reported.ObjectiveTo describe the distribution of SOD1:c.118A and SOD1:c.52T in 222 breeds.AnimalsDNA from 33,747 dogs was genotyped at SOD1:c.118, SOD1:c.52, or both. Spinal cord sections from 249 of these dogs were examined.MethodsRetrospective analysis of 35,359 previously determined genotypes at SOD1:c.118G>A or SOD1:c.52A>T and prospective survey to update the clinical status of a subset of dogs from which samples were obtained with a relatively low ascertainment bias.ResultsThe SOD1:c.118A allele was found in cross-bred dogs and in 124 different canine breeds whereas the SOD1:c.52T allele was only found in Bernese Mountain Dogs. Most of the dogs with histopathologically confirmed degenerative myelopathy were SOD1:c.118A homozygotes, but 8 dogs with histopathologically confirmed degenerative myelopathy were SOD1:c.118A/G heterozygotes and had no other sequence variants in their SOD1 amino acid coding regions. The updated clinical conditions of dogs from which samples were obtained with a relatively low ascertainment bias suggest that SOD1:c.118A homozygotes are at a much higher risk of developing degenerative myelopathy than are SOD1:c.118A/G heterozygotes.Conclusions and Clinical ImportanceWe conclude that the SOD1:c.118A allele is widespread and common among privately owned dogs whereas the SOD1:c.52T allele is rare and appears to be limited to Bernese Mountain Dogs. We also conclude that breeding to avoid the production of SOD1:c.118A homozygotes is a rational strategy.

Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

“…The pathological features of DM are similar to the pathological features of ALS (17)(18)(19)(20)(21)(22). DM has been confirmed in over 24 breeds (16,23) and presumptively reported in another nine breeds (16). In a previous study of canine SOD1, a SOD1:c.118G > A transition was identified that leads to a nonsynonymous substitution (E40K) in the homologous codon to the human E40G mutation (17).…”

“…Homozygosity for the variant allele was associated with risk of developing DM in five dog breeds (17). A separate SOD1 missense mutation has been discovered in Bernese Mountain Dogs, but has only been detected in that specific breed so far (23,24). Biochemical characterization of the two canine SOD1 mutant proteins indicated the increased propensity to form protein aggregates with retained enzymatic activity, supporting a toxic gain-of-function role in canine DM similar to that role in human ALS (25).…”

“…Of the tested dogs, 49% were homozygous for the ancestral allele (G), 24% were homozygous for the risk allele (A), and 27% were heterozygous (GA), but the frequency of the SOD1 risk allele was highly variable between breeds (23). In the Pembroke Welsh Corgi (PWC) breed, we have been able to confirm DM through histopathology in 53 phenotypically affected dogs; all of these dogs were homozygous for the SOD1 risk allele (23). We noted that among PWCs with two copies of the SOD1 risk allele, there were examples of dogs developing DM at a relatively early age (7-9 y), whereas others reached 15 y of age without any signs of DM.…”

“…We noted that among PWCs with two copies of the SOD1 risk allele, there were examples of dogs developing DM at a relatively early age (7-9 y), whereas others reached 15 y of age without any signs of DM. Similarly, all 42 Boxers with DM confirmed through histopathology were homozygous for the SOD1 risk allele (23); however, in contrast to the PWC, there were few examples of Boxers homozygous for the SOD1 mutation that reached old age (>11 y) without developing signs of DM.…”

“…Samples for genetic mapping were collected by primary care or specialist veterinarians and sent to the University of Missouri or the Broad Institute, obtained from dogs brought to the University of Missouri for euthanasia and necropsy or collected in the Canine Health Information Center DNA Bank (offa.org/chicdnabank.html). DNA was extracted from whole blood or buccal swabs as previously described (23). A presumptive diagnosis of DM was based on clinical signs, and the diagnosis was confirmed by histopathology showing a characteristic pattern of axonal degeneration, myelin loss, and gliosis in the thoracic spinal cord (16).…”