Cerebellar degeneration with myositis (Inflammatory myositis)

Gene: SLC25A12

Transmission: Likely autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Dutch Shepherd mutation: Substitution, SLC25A12 gene, c.1046 T>C, p.(L349P), chr.36.

Nova Scotia Duck Tolling Retriever mutation: Substitution, SLC25A12 gene, c.1337 C>T, p.(P446L), chr.36.

Medical system: Muscular, nervous

Breeds: Dutch Shepherd, Nova Scotia Duck Tolling

Age of onset of symptoms: 3-9 months for the Dutch Shepherd, 10 weeks to months for the Nova Scotia Duck Tolling Retriever.

A disease phenotype of progressive weakness involving inflammatory myopathy (myositis) and generalized muscle atrophy was observed in young animals within a Dutch Shepherd dog pedigree. Molecular analysis revealed a mutation within the SLC25A12 gene as the likely cause of the disease. The SLC25A12 gene codes for the aspartate-glutamate carrier 1 protein (AGC1) involved in mitochondrial transport of glutamate and the oxidative state of the cell. The described results in an oxidized intermitochondrial environment in muscle cells which would account for the observed inflammatory myopathy phenotype. A survey of 130 unrelated Dutch Shepherd dogs did not reveal the mutation outside of the pedigree in question.

A disease phenotype involving cerebellar signs of ataxia and hypermetria with variable presentation of muscle weakness and inflammatory myopathy was observed in Nova Scotia Duck Tolling Retriever litters. Molecular characterization again identified the SLC25A12 as harboring a causative mutation, albeit at a different site than seen in the Dutch Shepherd dog breed. Survey studies of 533 animals showed a carrier frequency of 7.1% in the European NSDTR population and a carrier frequency of 2.7% within the North American NSDTR population.

With this genetic information available, DNA tests can now be used to identify carrier animals in the process of eliminating the disease and eventually the mutation from affected breeds.

References:

OMIA link: [2294-9615]

Stee K, Van Poucke M, Lowrie M, et al. (2023) Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med. [pubmed/37341581]

Christen M, Rupp S, Van Soens I, et al. (2022) SLC25A12 missense variant in Nova Scotia Duck Tolling Retrievers affected by cerebellar degeneration-myositis complex (CDMC). Genes (Basel) 13:1223. [pubmed/35886006]

Shelton GD, Minor KM, Li K, et al. (2019) A mutation in the mitochondrial aspartate/glutamate carrier leads to a more oxidizing intramitochondrial environment and an inflammatory myopathy in Dutch shepherd dogs. J Neuromuscul Dis 6:485-501. [pubmed/31594244]

Contributed by: Victoria Blouin and Ariane Vézina, Class of 2028, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).