A Mutation in the Mitochondrial Aspartate/Glutamate Carrier Leads to Intramitochondrial Oxidation and an Inflammatory Myopathy in Dutch Shepherd Dogs

Inflammatory myopathies are a group of diseases characterized by infiltration of inflammatory cells into muscle. Young dogs from a small pedigree were evaluated for muscle weakness and atrophy. Muscle biopsies confirmed inflammation. Infiltration of T-lymphocytes and upregulation of MHC1 confirmed an immune-mediated myositis. Whole genome resequencing identified a variant in the SLC25A12 gene, resulting in a leucine to proline substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broadspectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress. This is the first description of a mitochondrial transporter mutation associated with a metabolic defect and an inflammatory myopathy.