821: Phenotypic Characterization and Mapping Genes Associated with Canine Degenerative Myelopathy in the Boxer Dog

Grant Status: Closed

Grant Amount: $176,272
Dr. Joan R. Coates, DVM, University of Missouri, Columbia
April 1, 2007 - March 31, 2010
Breed(s): Boxer
Research Program Area: Prevention

Project Summary

Degenerative myelopathy (DM) is a disease of the spinal cord causing progressive weakness and paralysis in the rear legs and later affect the front legs. Though commonly reported in German Shepherd Dogs (GSD), high disease prevalence also exists in other breeds, such as Cardigan and Pembroke Welsh Corgis (PWC), Rhodesian Ridgebacks (RR), and Boxer dogs. The increased risk in specific breeds suggests a significant genetic predisposition and adds power to mapping genetic risk factors. The purpose of this proposal was to map genes associated with DM in the Boxer or PWC. The researchers proposed characterizing the phenotype in the Boxer using sequential antemortem neurodiagnostic testing, and neuropathology. A small subset of 6 of the proposed 10 dogs has been characterized by the principal investigator, to determine if the phenotype and clinical progression is identical to that seen in the PWC. Clinical progression was followed with neurodiagnostic testing and histopathologic studies of the spinal cord, and peripheral nerve and muscles. In total, 6 Boxers had complete necropsy of the brain and spinal cord and an additional 16 dogs had sections of spinal cord evaluated. Onset of clinical signs initially began in the spinal cord affecting the hind limbs but as the disease progressed nerve and muscle involvement became apparent and eventually the fore limbs. Histopathology revealed lesions most severe in the dorsolateral portion of the thoracic spinal cord. In Boxers more severely affected, pathology was evident also in the cervical and lumbar spinal cord segments. Genome-wide association mapping using the SNP array was planned to identify a genomic location associated with DM in affected and healthy dogs from either the Boxer or PWC breed. Due to the faster submission of samples from PWCs, a genome-wide association was performed in the PWC. Promising results had been achieved with 38 affected and 17 healthy controls in identifying a major risk factor. Resequencing of a candidate gene at this location revealed a missense mutation in the superoxide dismutase 1 (SOD1) gene. Homozygosity for the mutant allele was associated with DM in 5 breeds which segregate for DM (Boxers, PWCs, RRs, Chesapeake Bay Retrievers and GSD). To further verify the localization of the DM mutation, the area was fine mapped in these breeds. All 5 breeds shared a haplotype surrounding the mutation, with no other concordant haplotype in the region, thus providing stronger evidence that the determined mutation underlies the disease phenotype. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss in distinct regions of the spinal cord and inclusions that bind anti-SOD1 antibodies. Such inclusions are also a hallmark feature of some forms of amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations. ALS [Lou Gehrig's disease] is an adult-onset, progressive paralysis of humans characterized by distinct loss of motor neurons and sclerosis of the spinal cord. Mutations in the SOD1 gene cause some forms of familial ALS. The researchers have completed development of a DNA test to identify dogs at risk in collaborations with the Animal Molecular Genetics Laboratory, MU Veterinary Medical Diagnostic Laboratory and Orthopedic Foundation for Animals. The researchers have performed another mapping using the PWC breed in search of additional associations. Genome-wide association showed four regions of interest, but none of these regions showed genome-wide significance. They plan to continue to collect more old healthy PWCs homozygous for the SOD1 mutation and genotype an additional number of dogs to reach genome-wide significance before starting fine-map. A similar study for modifiers using GWA will be performed in the Boxer breed as part of the CHF grant 1271: Mapping of Additional Genes Associated with Canine Degenerative Myelopathy. These two datasets will then be analyzed together.

Publication(s)

Awano T, Johnson GS, Wade C, Katz ML, Johnson GC, Taylor JF, Perloski M, Long S, March PA, Olby NJ, Khan S, O'Brien DP, Lindblad-Toh K, Coates JR. Genome-wide association analysis reveals a SOD1 missense mutation canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2009;106 (8):2794-2799. Accepted (December 12, 2008) Early online release February 2, 2009. One of the 30 most read papers in February 2009. Selected as one of the highlighted publications "In This Issue" section. March PA, Coates JR, Abyad R, Williams DA, O'Brien DP, Olby NJ, Keating JH, Oglesbee M. Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs. Veterinary Pathology, 2009;46:241-250. Coates JR, March PA, Ogelsbee M, Ruaux CG, Olby NL, Berghaus R, O'Brien DP, Johnson GS, Williams DA. Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. Journal of Veterinary Internal Medicine, 2007;21:1323-1331. Zeng R, Coates JR, Johnson GC, Katz ML, Taylor JF, Awano T, Khan S, Villamil A, Hahn AW, Lindblad-Toh K, Johnson GS. The degenerative myelopathy-associated A allele at SOD1:c.188 occurs in many dog breeds. Journal of the American Veterinary Medical Association. In progress Related Book Chapters: Coates, J.R., Wininger, F.A., 2010, Canine Degenerative Myelopathy. Veterinary Clinics of North America: Small Animal Practice 40, 929-950. Coates JR. Degenerative myelopathy. In: Tilley TP, Smith FWK (eds.) Blackwell's 5-minute Veterinary Consult Canine and Feline 4th ed. Blackwell Publishing Professional Ames, IA, pp.340-341, 2007. Coates JR. Degenerative myelopathy. In: C�t� E (ed). Clinical Veterinary Advisor: Dogs and Cats, Mosby, pp. 279-280, 2006. Coates JR. Degenerative myelopathy. In: Tilley TP, Smith FWK (eds.) Blackwell's 5-minute Veterinary Consult Canine and Feline 5th ed. Blackwell Publishing Professional Ames, IA , in press 2010.

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