title: Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis.
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.
authors.affiliation: Department of Veterinary Pathobiology, Mason Eye Institute, and Division of Animal Sciences, University of Missouri, Columbia MO 65211, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Awano
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wade
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.forename: Gayle C
authors.initials: GC
authors.lastname: Johnson
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.forename: Michele
authors.initials: M
authors.lastname: Perloski
authors.forename: Tara
authors.initials: T
authors.lastname: Biagi
authors.forename: Izabella
authors.initials: I
authors.lastname: Baranowska
authors.forename: Sam
authors.initials: S
authors.lastname: Long
authors.forename: Philip A
authors.initials: PA
authors.lastname: March
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Olby
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.forename: Shahnawaz
authors.initials: S
authors.lastname: Khan
authors.forename: Dennis P
authors.initials: DP
authors.lastname: O'Brien
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Joan R
authors.initials: JR
authors.lastname: Coates
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D016678:Genome; D055106:Genome-Wide Association Study; D006720:Homozygote; D007150:Immunohistochemistry; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D017931:DNA Primers; D013482:Superoxide Dismutase