01271A: Mapping of Additional Genes Associated with Canine Degenerative Myelopathy
Grant Status: Closed
Project SummaryDegenerative myelopathy (DM) is a fatal disease of the spinal cord causing progressive paralysis in mature dogs. In grant 821, we performed genome-wide association mapping and identified a SOD1gene mutation, which is present in many breeds. A DNA test can now identify dogs at risk of developing DM, although many dogs that have the mutation never develop clinical symptoms. The availability of the DM test has raised questions that must be answered before this test can be optimally used by dog breeders. These include: Are there genetic modifiers that could explain why some dogs with the mutation develop DM at 8 years of age while other 15-year-old dogs with the same mutation remain symptom free? Are there other mutations in the SOD1 gene or elsewhere that can cause DM or DM-like diseases? We are making good progress on answering these questions, having preliminary data about modifier loci for both the Boxer and Pembroke Welsh Corgi breed that is being further evaluated. We have determined that the onset distribution is more tightly clustered in Boxers than in Pembroke Welsh Corgis (PWC), potentially making it harder to map modifier loci in Boxers than PWCs. The Boxer GWAs resulted only in two nonsignificant loci. Outside the scope of this grant we will now continue to collect samples for a modifier screen in a larger sample size. Three loci on chromosomes 25, 27 and 37 were significantly associated with ALS in PWC. The two loci on chromosomes 27 and 37 are well defined and each contains an excellent candidate gene expressed in the brain. All identified variants are currently being evaluated for functional potential. Once the most associated variants with the strongest association have been identified from the validation genotyping based on the targeted resequencing we will perform functional studies. We conclude that it is highly unlikely that cis-acting genetic modifiers contribute to the apparent differences in susceptibility to DM in the two Pembroke Welsh Corgis we studied. During the time-frame of this grant we also investigated histopathology of spinal cords and have now confirmed DM in over 20 purebred and mixed breed dogs. We identified a new SOD1 mutation in Bernese Mountain Dogs and currently are investigating a GSD with DM for a mutation in a different gene. Identification of additional genes will also give us a better understanding of the disease and allow development of potential treatment strategies.
Publication(s)- Shelton GD, Johnson GC, Johnson GS, O'Brien DP, Katz ML, Pasayco JP, Chang BJ, Mizisin AP, Coates JR. Peripheral nerve and muscle pathology in Pembroke Welsh Corgis and Boxers with degenerative myelopathy and a missense mutation in the superoxide di
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