{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T09:46:47Z","timestamp":1784022407820,"version":"3.55.0"},"reference-count":22,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T00:00:00Z","timestamp":1729814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Orthopedic Foundation for Animals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Canine multiple system degeneration (CMSD) is an early onset, progressive movement disorder affecting Kerry Blue Terriers and Chinese Crested dogs. The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus, and substantia nigra. CMSD is inherited as an autosomal recessive trait in both dog breeds. Previous linkage mapping localized the CMSD locus to a 15 MB region on canine chromosome 1 (CFA1). Next-generation sequencing was used to generate whole-genome sequences from the DNA of an affected dog from each breed. The resulting sequence reads were aligned to the NCBI canine reference genome (build 3.1). Among the homozygous sequence variants within the CFA1 target region, a nonsense variant in exon 15 of SERAC1 was identified in the affected Kerry Blue Terrier, while in the Chinese Crested dog, a 4 bp deletion in the SERAC1 exon 4 acceptor splice site was found. RT-PCR showed that this deletion resulted in exon 4 skipping. Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested dogs for the respective breed-specific SERAC1 variants showed complete concordance between genotype and disease phenotype. Genotype\u2013phenotype concordance was also observed in offspring generated by cross breeding between SERAC1-heterozygous Kerry Blue Terrier and Chinese Crested dogs, with only the compound heterozygotes exhibiting the disease phenotype, further confirming the recessive inheritance of CMSD. Variants in human SERAC1 are associated with disorders with a range of ages of disease onset and patterns of clinical signs, but that are all characterized by movement abnormalities similar to those of the dogs with CMSD. Canine CMSD could serve as a valuable model to elucidate the mechanisms underlying SERAC1-deficiency disorders and to evaluate potential therapeutic interventions.<\/jats:p>","DOI":"10.3390\/genes15111378","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:15:02Z","timestamp":1730088902000},"page":"1378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1"],"prefix":"10.3390","volume":"15","author":[{"given":"Rong","family":"Zeng","sequence":"first","affiliation":[{"name":"IWK Health, Pathology and Laboratory Medicine, 5850 University Avenue, Halifax, NS B3K 6R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juyan","family":"Guo","sequence":"additional","affiliation":[{"name":"Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9231-8758","authenticated-orcid":false,"given":"Garrett","family":"Bullock","sequence":"additional","affiliation":[{"name":"Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2225-3204","authenticated-orcid":false,"given":"Gary S.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2582-9187","authenticated-orcid":false,"given":"Martin L.","family":"Katz","sequence":"additional","affiliation":[{"name":"Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"},{"name":"Neurodegenerative Diseases Research Laboratory, Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/jhered\/esi086","article-title":"Genetic Mapping of Canine Multiple System Degeneration and Ectodermal Dysplasia Loci","volume":"96","author":"Johnson","year":"2005","journal-title":"J. Hered."},{"key":"ref_2","first-page":"1119","article-title":"Hereditary Cerebellar Cortical and Extrapyramidal Nuclear Abiotrophy in Kerry Blue Terriers","volume":"168","author":"deLahunta","year":"1976","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/77060","article-title":"Familial Parkinson Disease Gene Product, Parkin, Is a Ubiquitin-Protein Ligase","volume":"25","author":"Shimura","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3988\/jcn.2022.18.3.259","article-title":"Clinical Aspects of the Differential Diagnosis of Parkinson\u2019s Disease and Parkinsonism","volume":"18","author":"Shin","year":"2022","journal-title":"J. Clin. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/B978-0-12-804766-8.00016-9","article-title":"Recognizing and Treating Atypical Parkinson Disorders","volume":"167","author":"Armstrong","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1136\/jnnp-2016-314956","article-title":"Predictors of Survival in Progressive Supranuclear Palsy and Multiple System Atrophy: A Systematic Review and Meta-Analysis","volume":"88","author":"Glasmacher","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Keir, G., Roytman, M., Mashriqi, F., Shahsavarani, S., and Franceschi, A.M. Atypical Parkinsonian Syndromes: Structural, Functional, and Molecular Imaging Features. AJNR Am. J. Neuroradiol., 2024. in press.","DOI":"10.3174\/ajnr.A8313"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.bbrc.2004.12.038","article-title":"A Mutation in the CLN8 Gene in English Setter Dogs with Neuronal Ceroid-Lipofuscinosis","volume":"327","author":"Katz","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","unstructured":"Wortmann, S.B., de Brouwer, A.P.M., Wevers, R.A., and Morava, E. (1993). SERAC1 Deficiency, University of Washington."},{"key":"ref_10","first-page":"377","article-title":"Canine Chorea Due to Striatocerebellar Degeneration of Unknown Etiology","volume":"108","author":"Metler","year":"1946","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabl6992","DOI":"10.1126\/scitranslmed.abl6992","article-title":"SERAC1 Is a Component of the Mitochondrial Serine Transporter Complex Required for the Maintenance of Mitochondrial DNA","volume":"14","author":"Fang","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/ng.2325","article-title":"Mutations in the Phospholipid Remodeling Gene SERAC1 Impair Mitochondrial Function and Intracellular Cholesterol Trafficking and Cause Dystonia and Deafness","volume":"44","author":"Wortmann","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_13","first-page":"388","article-title":"Two Turkish Siblings with MEGDEL Syndrome Due to Novel SERAC1 Gene Mutation","volume":"57","author":"Unal","year":"2015","journal-title":"Turk. J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e815","DOI":"10.1002\/mgg3.815","article-title":"Identification of a Novel Splice Site Mutation in the SERAC1 Gene Responsible for the MEGDHEL Syndrome","volume":"7","author":"Snanoudj","year":"2019","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref_15","first-page":"3505","article-title":"A Novel Mutation in the SERAC1 Gene Correlates with the Severe Manifestation of the MEGDEL Phenotype, as Revealed by Whole-Exome Sequencing","volume":"19","author":"Alagoz","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1136\/jmedgenet-2017-104622","article-title":"SERAC1 Deficiency Causes Complicated HSP: Evidence from a Novel Splice Mutation in a Large Family","volume":"55","author":"Roeben","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_17","first-page":"1","article-title":"SERAC1 Deficiency- A New Phenotype","volume":"24","author":"Martins","year":"2023","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.pediatrneurol.2020.03.009","article-title":"MEGDEL Syndrome","volume":"110","author":"Finsterer","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/ana.25110","article-title":"Progressive Deafness-Dystonia Due to SERAC1 Mutations: A Study of 67 Cases","volume":"82","author":"Maas","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ejmg.2017.07.013","article-title":"Novel Mutations in SERAC1 Gene in Two Indian Patients Presenting with Dystonia and Intellectual Disability","volume":"61","author":"Lingappa","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"554","DOI":"10.5334\/tohm.445","article-title":"Adult-Onset Generalized Dystonia as the Main Manifestation of MEGDEL Syndrome","volume":"8","author":"Giron","year":"2018","journal-title":"Tremor Other Hyperkinet Mov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e200067","DOI":"10.1212\/NXG.0000000000200067","article-title":"Novel SERAC1 Variant Presenting with Adult-Onset Extrapyramidal Dystonia-Parkinsonism Phenotype: A Case Report","volume":"9","author":"Ashton","year":"2023","journal-title":"Neurol. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:20:54Z","timestamp":1760113254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,25]]},"references-count":22,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["genes15111378"],"URL":"https:\/\/doi.org\/10.3390\/genes15111378","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,25]]}}}