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.

Immunohistochemical Observation of Canine Degenerative Myelopathy in Two Pembroke Welsh Corgi Dogs

“…Several causes of DM have been proposed, including immunologic [5,19], metabolic [9], and genetic mechanisms [4]. Recently, Awano et al indicated that a superoxide dismutase 1 (SOD1) mutation (c.118G>A) is associated with canine DM in several breeds including PWC [4,17].…”

Le chien dans la pathologie et la génétique comparée: exemples de maladies et de gènes partagés entre l'homme et le chien

“…Concernant les maladies à composantes génétiques « simples » ou supposées simples, de nombreux travaux font actuellement état de l'identification de gènes responsables d'affections partagées entre l'homme et le chien, comme, par exemple, des rétinopa-thies (Wilk et al 2008), la sclérose amyothrophique latérale (Awano et al 2009), des maladies cardiaques (Meurs et al 2010), les lipofuscinoses neuronales canines (Abitbol et al 2010 ;Katz et al 2011), les épilepsies (Lohi et al 2005 ;Sepalla et al 2011), des maladies dermatologiques telle que l'ichtyose (Grall et al 2012), ou encore des anomalies comme le phénotype sans poil des chiens nus (Drogemuller et al, 2008).…”

Cell-Based Therapy for Neural Disorders — Anticipating Challenges

“…A relevant animal model should show behavioral deficits that resemble symptoms in patients. Some animal models reproduce the human condition quite faithfully, as in the case of familial ALS in which the same mutations that are found in human disease produces a similar progressive loss of neurons and motor function in dogs [22], rats [23], and mice [24]. Models of injury, such as spinal cord injury and stroke, can be induced in animals and are used extensively to evaluate treatments for both acute and chronic dysfunction in patients.…”