Categories: Nervous system phene , Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612949 (trait) , 603667 (gene)

Mendelian trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: CDMC

Species-specific name: Cerebellar degeneration-myositis complex, inflammatory myopathy

History: Shelton et al. (2019): "This report is the first description of a SLC25A12 variant resulting in an inflammatory myopathy in any species and reveals a complex pattern of metabolomic changes associated with this variant."

Molecular basis: Shelton et al. (2019): "After filtering these protein-coding homozygous variants against a dog genetic variant database . . . only one was unique to the sequenced case; a leucine to proline mutation (chr36:g.16,219,219A>G; c.1046T>C; p.L349P) within the SLC25A12 gene." SLC25A12 encodes the solute carrier family 25 member 2, a mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle. Shelton et al. (2019) demonstrated that recombinant mutant SLC25A12 showed a strong impairment of transport activity compared to the wildtype protein. "As a result of this impaired transport, mitochondrial redox becomes more oxidizing with fewer reducing equivalents imported into the mitochondria via NADH. MAS defects lead to progressive intramitochondrial oxidation as NADH/NAD+ and NADPH/NADP+ ratios fall. The fall in intramitochondrial NADH/NAD+ ratio results in a highly oxidizing and proinflammatory muscle milieu. This is in contrast to the primary disorders of oxidative phosphorylation like complex I and complex IV deficiency leading to Leigh Syndrome, in which the mitochondria cannot consume the NADH that comes in and the intramitochondrial NADH/NAD+ ratio rises." (Shelton et al. 2019) Christen et al. (2022) studied two litters of Nova Scotia Duck Tolling Retrievers, in which a total of four puppies were affected by a phenotype designated as cerebellar degeneration-myositis complex (CDMC). Whole genome sequencing of an affected dog at 29.1x coverage and comparison to 565 control genomes revealed 6 homozygous and 88 heterozygous private protein-changing variants. The authors identified a homozygous missense variant in SLC25A12 as the most likely candidate for the observed neurologic/neuromuscular phenotype. The identified variant was Chr36:16,504,064G>A (UU_Cfam_GSD_1.0 assembly) or XM_038584842.1:c.1337C>T or XP_038440770.1:(p.Pro446Leu). Genotypes at this variant showed the expected co-segregation with the phenotype in the available families and were perfectly associated with the disease phenotype in independently collected cohorts of 380 European and 153 North American Nova Scotia Duck Tolling Retrievers. The mutant allele frequencies in the European and North American cohorts were 3.6% abd 1.3%, respectively.

Clinical features: Shelton et al. (2019) reported in Dutch Shepherd dogs with the p.L349P variant: "Five related Dutch Shepherd dogs with progressive muscle weakness and generalized muscle atrophy beginning at 3 to 9 months of age were euthanized by 2 years of age. Clinical signs included muscle tremors, pelvic limb stiffness, weakness progressing to inability to walk, and severe muscle atrophy. Serum CK activity was moderately elevated (ranging from 800–2,500 IU/L (reference values <200 IU/L) in all affected dogs, indicating myofiber damage. As far as could be determined, affected dogs did not have behavioral abnormalities or seizure activity, interacted with littermates and other dogs, and were visual with no ocular abnormalities noted. As myopathic changes predominated, extensive evaluations by a veterinary neurologist for central nervous system disease or by an ophthalmologist for ocular disease were not performed." Christen et al. (2022) reported in 4 Nova Scotia Duck Tolling Retrievers with the p.P446L variant: "Age of onset of neurological signs was between 10 weeks and 6 months. Clinical abnormalities were restricted to the neuromuscular system in all four dogs. Neurological examination showed generalized ataxia and hypermetria, which was more pronounced in the pelvic limbs in all four dogs. Intentional head tremor was present in one dog. In two dogs, generalized neuromuscular weakness became apparent after 1 month, characterized by exercise intolerance, episodic collapse, stiff gait, and bunny hopping. Hopping was delayed in four limbs in three dogs, menace responses were absent in one dog, and decreased withdrawal reflexes were found in four limbs of three dogs." ... "Blood examination showed increases in serum creatine kinase concentrations in all four dogs (between 3 and 25 times greater than the upper reference limit). An EMG showed mild spontaneous activity in peripheral limb muscles. MRI of the brain in the same dog showed bilateral symmetrical lesions in the cerebellum and multifocal lesions in the masticatory muscles."

Pathology: Shelton et al. (2019): "Histopathology of muscle biopsies confirmed an inflammatory myopathy and immune-mediated, infectious and dystrophic disorders were considered." Christen et al. (2022): "Muscle and nerve biopsies showed a fiber-invasive lymphohistiocytic myositis without evidence of intracellular infectious agents on histology and tissue PCR. The only other abnormality seen on postmortem examination was severe cerebellar nuclear degeneration. Based on the available clinical and diagnostic findings, we tentatively termed the phenotype of the four affected dogs cerebellar degeneration—myositis complex (CDMC)."

Breeds: Dutch Shepherd (Dog) (VBO_0200463), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: