{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:25:42Z","timestamp":1790267142725,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle\/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G&gt;A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.<\/jats:p>","DOI":"10.3390\/genes11070774","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:45:31Z","timestamp":1594374331000},"page":"774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED)"],"prefix":"10.3390","volume":"11","author":[{"given":"Jasmin","family":"Nessler","sequence":"first","affiliation":[{"name":"Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover Foundation, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Hug","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. J.","family":"Mandigers","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A. J.","family":"Leegwater","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-0041","authenticated-orcid":false,"given":"Vidhya","family":"Jagannathan","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anibh M.","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1485-1610","authenticated-orcid":false,"given":"Marco","family":"Rosati","sequence":"additional","affiliation":[{"name":"Section of Clinical and Comparative Neuropathology, Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universit\u00e4t, 80539 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaspar","family":"Matiasek","sequence":"additional","affiliation":[{"name":"Section of Clinical and Comparative Neuropathology, Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universit\u00e4t, 80539 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian C.","family":"Sewell","sequence":"additional","affiliation":[{"name":"Biocontrol, Labor f\u00fcr Veterin\u00e4rmedizinische Diagnostik, 55218 Ingelheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Kornberg","sequence":"additional","affiliation":[{"name":"AniCura Tierklinik Trier GbR, 54294 Trier, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4776-0405","authenticated-orcid":false,"given":"Marina","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Tierklinik Stommeln, 50259 Puhlheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0760-6067","authenticated-orcid":false,"given":"Petra","family":"Wolf","sequence":"additional","affiliation":[{"name":"Nutritional Physiology and Animal Nutrition, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7094-1947","authenticated-orcid":false,"given":"Andrea","family":"Fischer","sequence":"additional","affiliation":[{"name":"Section of Neurology, Clinic of Small Animal Medicine, Ludwig-Maximilians-Universit\u00e4t, 80539 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Tipold","sequence":"additional","affiliation":[{"name":"Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover Foundation, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-4880","authenticated-orcid":false,"given":"Tosso","family":"Leeb","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s11910-019-0958-3","article-title":"Paroxysmal Movement Disorders: Recent Advances","volume":"19","author":"Xu","year":"2019","journal-title":"Curr. 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