{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:14:01Z","timestamp":1787170441832,"version":"build-2736575974"},"reference-count":57,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T00:00:00Z","timestamp":1569283200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neuromuscular Diseases"],"published-print":{"date-parts":[[2019,10,17]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Whole genome resequencing identified a pathological 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, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3233\/jnd-190421","type":"journal-article","created":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T14:12:11Z","timestamp":1569593531000},"page":"485-501","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":18,"title":["A Mutation in the Mitochondrial Aspartate\/Glutamate Carrier Leads to a More Oxidizing Intramitochondrial Environment and an Inflammatory Myopathy in Dutch Shepherd Dogs"],"prefix":"10.1177","volume":"6","author":[{"given":"G. Diane","family":"Shelton","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie M.","family":"Minor","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefeng","family":"Li","sequence":"additional","affiliation":[{"name":"The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C.","family":"Naviaux","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Monk","sequence":"additional","affiliation":[{"name":"The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Guzik","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling T.","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Porcelli","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruggiero","family":"Gorgoglione","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco M.","family":"Lasorsa","sequence":"additional","affiliation":[{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Leegwater","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, 3508, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio M.","family":"Persico","sequence":"additional","affiliation":[{"name":"Interdepartmental Program \u201cAutism 0\u201390\u201d, \u201cG. 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