Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis
- Departments of aVeterinary Pathobiology and
- kVeterinary Medicine and Surgery,
- dMason Eye Institute, and
- eDivision of Animal Sciences, University of Missouri, Columbia MO 65211;
- bBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02141;
- cCenter for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston MA 02114;
- fDepartment of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Biomedical Center, Box 597, SE-751 24 Uppsala, Sweden;
- gSection of Neurology and Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104;
- hDepartment of Clinical Sciences, Tufts University, North Grafton, MA 01536;
- iDepartment of Clinical Sciences, North Carolina State University, Raleigh, NC 27606;
- jDepartment of Pathology, University of California at San Diego, La Jolla, CA 92093; and
- lDepartment of Medical Biochemistry and Microbiology, Uppsala University, Box 597, 751 24 Uppsala, Sweden
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Communicated by James E. Womack, Texas A&M University, College Station, TX, December 10, 2008 (received for review June 17, 2008)

Abstract
Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.
Footnotes
- 1To whom correspondence should be addressed. E-mail: johnsongs{at}missouri.edu
Author contributions: K.L.-T. and J.R.C. designed research; T.A., M.L.K., G.C.J., M.P., T.B., I.B., G.D.S., S.K., D.P.O., and J.R.C. performed research; G.S.J., S.L., P.A.M., N.J.O., K.L.-T., and J.R.C. contributed new reagents/analytic tools; G.S.J., C.M.W., and J.F.T. analyzed data; and G.S.J., C.M.W., M.L.K., G.C.J., J.F.T., K.L.-T., and J.R.C. wrote the paper.
Conflict of interest statement: The University of Missouri has applied for a patent covering the use of markers for the SOD1 mutation for the diagnosis of DM or for marker-assisted selective breeding of dogs. G.S.J., J.R.C., K.L.-T., and C.M.W. are listed as inventors in this application.
Freely available online through the PNAS open access option.
- © 2009 by The National Academy of Sciences of the USA
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