Degenerative Myelopathy, modifying gene

 

Gene: SP110

Transmission: Autosomal, dominant

For an autosomal dominant genetic disease, an animal must have at least one copy of the mutation in question to be at risk of developing the disease.  Animals with two copies of the mutation generally have more severe symptoms and an earlier onset of the disease than animals with just one copy of the mutation.  One or both of the parents of an animal with the mutation has one or two copies of the mutation.  Animals that have one or two copies of the mutation can pass the mutation on to future generations.

Mutation: Substitution, SP110 gene;  chr.25:45,443,320, A>G, exon9

Medical system: Neurologic, muscular

Breed: Cardigan Welsh Corgi, Pembroke Welsh Corgi

Age of onset of symptoms: 7 to 9 years

Degenerative myelopathy (DM) is a neurodegenerative disease seen in numerous dog breeds.  It is equivalent to the human disease Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease.  DM is a progressive disease that affects the white matter of the spinal cord. The average time of onset of clinical signs in the dog is 9 years, however there is considerable variation between dogs. Affected dogs usually start showing symptoms of progressive muscular atrophy with initial loss of coordination of the hind limbs, and can lose mobility six months to two years after the onset of signs.  Pain is not associated with the progression of symptoms.  There is no treatment for the disease which can progress to the point that the animal is incontinent and eventually paraplegic.   Often the affected animal is euthanized for humanitarian reasons before these final stages.

DM is an autosomal recessive disease that displays variable penetrance.  Although a major genetic risk factor for dogs is a mutation within exon2 of the SOD1 gene (c.118, G>A), it is felt that depending on the breed of dog, additional genetic risk factors (modifying genes) exist that contribute to the time of onset and the rate of progression of the disease.  This is reminiscent of the genetic complexity of ALS in humans.

The Cardigan Welsh Corgi and Pembroke Welsh Corgi have a high frequency (over 30%) of the SOD1 mutation and individual animals that are M/M double mutant are susceptible to developing DM.  However, not all Welsh Corgis that are M/M for SOD1 will develop DM.  Indeed, animals that are M/M fall into two groups: those that develop DM between 7 and 9 years of age, and those that do not develop the disease by 15 years of age.  A modifying gene, SP110, was identified in the Welsh Corgi and a mutation in the gene was correlated with an increased risk of early onset of DM in M/M double mutant SOD1 Corgis.  SP110 codes for a nuclear protein that is involved in the nuclear matrix and the regulation of gene expression.

 

References:

OMIA link:  [0263-9615]

Ivansson EL, Megquir K, Kozyrev SV, et al.  (2016) Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy.  PNAS USA E3091-E3100. [pubmed/27185954]

Shelton GD, Johnson GC, O’Brien DP, et al. (2012) Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh corgis and boxers. J Neurol Sci. 318(1-2):55-64. [pubmed/22542607]