{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T15:58:27Z","timestamp":1781020707174,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T00:00:00Z","timestamp":1719705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Division of Comparative Medicine, Office of Research Infrastructure Programs","award":["1 K01 OD027058"],"award-info":[{"award-number":["1 K01 OD027058"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>(1) Background: An adult dog was presented to a board-certified veterinary neurologist for evaluation of chronic weakness, exercise intolerance and lactic acidemia. (2) Methods: A mitochondrial myopathy was diagnosed based on the histological and histochemical phenotype of numerous COX-negative muscle fibers. Whole-genome sequencing established the presence of multiple extended deletions in the mitochondrial DNA (mtDNA), with the highest prevalence between the 1\u201311 kb positions of the approximately 16 kb mitochondrial chromosome. Such findings are typically suggestive of an underlying nuclear genome variant affecting mitochondrial replication, repair, or metabolism. (3) Results: Numerous variants in the nuclear genome unique to the case were identified in the whole-genome sequence data, and one, the insertion of a DYNLT1 retrogene, whose parent gene is a regulator of the mitochondrial voltage-dependent anion channel (VDAC), was considered a plausible causal variant. (4) Conclusions: Here, we add mitochondrial deletion disorders to the spectrum of myopathies affecting adult dogs.<\/jats:p>","DOI":"10.3390\/ani14131946","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T04:53:27Z","timestamp":1719809607000},"page":"1946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-Allelic Mitochondrial DNA Deletions in an Adult Dog with Chronic Weakness, Exercise Intolerance and Lactic Acidemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-1359","authenticated-orcid":false,"given":"G. Diane","family":"Shelton","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-0234","authenticated-orcid":false,"given":"James R.","family":"Mickelson","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7510-2322","authenticated-orcid":false,"given":"Steven G.","family":"Friedenberg","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonah N.","family":"Cullen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaya M.","family":"Mehra","sequence":"additional","affiliation":[{"name":"VCA Animal Care Center of Sonoma County, Rohnert Park, CA 94928, 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 92093-0709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5472-5088","authenticated-orcid":false,"given":"Katie M.","family":"Minor","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrg1606","article-title":"Mitochondrial DNA mutations in human disease","volume":"6","author":"Taylor","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nrneurol.2013.126","article-title":"The clinical maze of mitochondrial neurology","volume":"9","author":"DiMauro","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s13311-018-00674-4","article-title":"Diagnosis and treatment of mitochondrial myopathies","volume":"15","author":"Ahmed","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/gim.2017.107","article-title":"Patient care standards for primary mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society","volume":"19","author":"Parikh","year":"2017","journal-title":"Genet. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ymgme.2022.05.001","article-title":"North American Mitochondrial Disease Consortium (NAMDC). Time to harmonize mitochondrial syndrome nomenclature and classification: A consensus from the North American Mitochondrial Disease Consortium (NAMDC)","volume":"136","author":"Emmanuele","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1093\/hmg\/10.20.2277","article-title":"Nuclear genetic defects of oxidative phosphorylation","volume":"10","author":"Shoubridge","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1056\/NEJMra022567","article-title":"Mitochondrial respiratory-chain diseases","volume":"348","author":"DiMauro","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1093\/brain\/awh259","article-title":"Mitochondrial disorders","volume":"127","author":"Zeviani","year":"2004","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/331717a0","article-title":"Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies","volume":"331","author":"Holt","year":"1988","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1212\/WNL.38.8.1339","article-title":"Deletions of mitochondrial DNA in Kearns-Sayre syndrome","volume":"38","author":"Zeviani","year":"1988","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1056\/NEJM198905183202001","article-title":"Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome","volume":"320","author":"Moraes","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/348651a0","article-title":"A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies","volume":"348","author":"Goto","year":"1990","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1006\/bbrc.1997.7167","article-title":"Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS","volume":"238","author":"Santorelli","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1136\/jmg.2004.020537","article-title":"Mutations of the mitochondrial ND1 gene as a cause of MELAS","volume":"41","author":"Kirby","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/0092-8674(90)90059-N","article-title":"Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation","volume":"61","author":"Shoffner","year":"1990","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vernau, K.M., Runstadler, J.A., Brown, E.A., Cameron, J.M., Huson, H.J., Higgins, R.J., Ackerley, C., Sturges, B.K., Dickinson, P.J., and Puschner, B. (2013). Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057195"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dr\u00f6gem\u00fcller, M., Letko, A., Matiasek, K., Jagannathan, V., Corlazzoli, D., Rosati, M., Jurina, K., Medl, S., G\u00f6dde, T., and Rupp, S. (2020). SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy. Genes, 11.","DOI":"10.3390\/genes11101215"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.nbd.2005.06.009","article-title":"Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b","volume":"21","author":"Li","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1038\/s41598-024-53314-7","article-title":"NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model","volume":"14","author":"Christen","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ymgme.2006.09.011","article-title":"Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency","volume":"90","author":"Cameron","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3233\/JND-190421","article-title":"A Mutation in the Mitochondrial Aspartate\/Glutamate Carrier Leads to a More Oxidizing Intramitochondrial Environment and an Inflammatory Myopathy in Dutch Shepherd Dogs","volume":"6","author":"Shelton","year":"2019","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1534\/g3.118.200084","article-title":"A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy","volume":"8","author":"Lepori","year":"2018","journal-title":"G3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/0300-9629(94)90236-4","article-title":"Canine mitochondrial myopathy associated with reduced mitochondrial mRNA and altered cytochrome c oxidase activities in fibroblasts and skeletal muscle","volume":"109","author":"Vijayasarathy","year":"1994","journal-title":"Comp. Biochem. Physiol. A Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mito.2022.02.001","article-title":"Mitochondrial DNA alterations in the domestic dog (Canis lupus familiaris) and their association with development of diseases: A review","volume":"63","author":"Kowal","year":"2022","journal-title":"Mitochondrion"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Baranowska, I., J\u00e4derlund, K.H., Nennesmo, I., Holmqvist, E., Heidrich, N., Larsson, N.G., Andersson, G., Wagner, E.G., Hedhammar, A., and Wibom, R. (2009). Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000499"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Meurs, K.M., Friedenberg, S.G., Olby, N.J., Condit, J., Weidman, J., Rosenthal, S., and Shelton, G.D. (2019). A QIL1 Variant Associated with Ventricular Arrhythmias and Sudden Cardiac Death in the Juvenile Rhodesian Ridgeback Dog. Genes, 10.","DOI":"10.3390\/genes10020168"},{"key":"ref_27","unstructured":"Dubowitz, V., Sewry, C.A., and Oldfors, A. (2021). Histological and histochemical stains and reactions. Muscle Biopsy: A Practical Approach, 5th ed, Elsevier."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, C., Wallerman, O., Arendt, M.L., Sundstr\u00f6m, E., Karlsson, \u00c5., Nordin, J., M\u00e4kel\u00e4inen, S., Pielberg, G.R., Hanson, J., and Ohlsson, \u00c5. (2021). A novel canine reference genome resolves genomic architecture and uncovers transcript complexity. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-01698-x"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Meadows, J.R.S., Kidd, J.M., Wang, G.D., Parker, H.G., Schall, P.Z., Bianchi, M., Christmas, M.J., Bougiouri, K., Buckley, R.M., and Hitte, C. (2023). Genome sequencing of 2000, canids by the Dog10K consortium advances the understanding of demography, genome function and architecture. Genome Biol., 24.","DOI":"10.1186\/s13059-023-03023-7"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"jkad117","DOI":"10.1093\/g3journal\/jkad117","article-title":"Whole Animal Genome Sequencing: User-friendly, rapid, containerized pipelines for processing, variant discovery, and annotation of short-read whole genome sequencing data","volume":"13","author":"Cullen","year":"2023","journal-title":"G3"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1093\/bioinformatics\/15.5.356","article-title":"Promoter2.0: For the recognition of PolII promoter sequences","volume":"15","author":"Knudsen","year":"1999","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-1-60761-854-6_5","article-title":"Identification of promoter regions and regulatory sites","volume":"674","author":"Solovyev","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0195-5616(03)00080-9","article-title":"Muscle and nerve biopsy","volume":"32","author":"Dickinson","year":"2002","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0195-5616(03)00078-0","article-title":"The clinical examination for neuromuscular disease","volume":"32","author":"Glass","year":"2002","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1086\/507132","article-title":"Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers","volume":"79","author":"Bua","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1113\/JP271212","article-title":"The ageing neuromuscular system and sarcopenia: A mitochondrial perspective","volume":"594","author":"Rygiel","year":"2016","journal-title":"J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s12306-011-0096-9","article-title":"Metabolic myopathies: Functional evaluation by different exercise testing approaches","volume":"95","author":"Volpi","year":"2011","journal-title":"Musculoskelet. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bbadis.2017.02.017","article-title":"Mitochondrial DNA maintenance defects","volume":"1863","author":"Craigen","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Varughese, J.T., Buchanan, S.K., and Pitt, A.S. (2021). The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease. Cells, 10.","DOI":"10.3390\/cells10071737"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fang, Y.d., Xu, X., Dang, Y.m., Zhang, Y.m., Zhang, J.p., Hu, J.-Y., Zhang, Q., Dai, X., Teng, M., and Zhang, D.-X. (2011). MAP4 Mechanism that Stabilizes Mitochondrial Permeability Transition in Hypoxia: Microtubule Enhancement and DYNLT1 Interaction with VDAC1. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028052"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s10020-023-00663-0","article-title":"DYNLT1 promotes mitochondrial metabolism to fuel breast cancer development by inhibiting ubiquitination degradation of VDAC1","volume":"29","author":"Huang","year":"2023","journal-title":"Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S1357-2725(02)00026-2","article-title":"Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74","volume":"34","author":"Schwarzer","year":"2002","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/j.bbamcr.2016.04.020","article-title":"VDAC2-specific cellular functions and the underlying structure","volume":"1863","author":"Naghdi","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6407","DOI":"10.1038\/onc.2008.308","article-title":"Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis","volume":"27","author":"Pinton","year":"2008","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1126\/science.1173275","article-title":"An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs","volume":"325","author":"Parker","year":"2009","journal-title":"Science"}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/14\/13\/1946\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:08:18Z","timestamp":1760108898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/14\/13\/1946"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,30]]},"references-count":45,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ani14131946"],"URL":"https:\/\/doi.org\/10.3390\/ani14131946","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,30]]}}}