{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T11:47:50Z","timestamp":1782733670866,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009716","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000}}],"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of <jats:italic>SELENOP<\/jats:italic> and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping &gt;600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. <jats:italic>Selenop<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the <jats:italic>SELENOP<\/jats:italic> gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009716","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T17:39:57Z","timestamp":1627925997000},"page":"e1009716","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3275-5929","authenticated-orcid":true,"given":"Matthias","family":"Christen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-5273","authenticated-orcid":true,"given":"Sandra","family":"H\u00f6gler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Kleiter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Leschnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4858-2188","authenticated-orcid":true,"given":"Corinna","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Thaller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-0041","authenticated-orcid":true,"given":"Vidhya","family":"Jagannathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-4880","authenticated-orcid":true,"given":"Tosso","family":"Leeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"pgen.1009716.ref001","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11910-021-01092-4","article-title":"Genetic ataxias: update on classification and diagnostic approaches","volume":"21","author":"N Witek","year":"2021","journal-title":"Curr Neurol Neurosci Rep"},{"key":"pgen.1009716.ref002","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ncl.2014.09.004","volume":"33","author":"U Akbar","year":"2015","journal-title":"Ataxia. Neurol Clin"},{"key":"pgen.1009716.ref003","doi-asserted-by":"crossref","first-page":"117082","DOI":"10.1016\/j.jns.2020.117082","article-title":"Natural history and epidemiology of the spinocerebellar ataxias: Insights from the first description to nowadays","volume":"417","author":"O Scott SS de","year":"2020","journal-title":"J Neurol Sci"},{"key":"pgen.1009716.ref004","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1007\/s12311-019-01052-2","article-title":"The classification of autosomal recessive cerebellar ataxias: a consensus statement from the Society for Research on the Cerebellum and Ataxias Task Force","volume":"18","author":"M Beaudin","year":"2019","journal-title":"Cerebellum"},{"key":"pgen.1009716.ref005","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.neurol.2016.04.005","article-title":"Classifications of neurogenetic diseases: An increasingly complex problem","volume":"172","author":"JM Vallat","year":"2016","journal-title":"Rev Neurol (Paris)."},{"key":"pgen.1009716.ref006","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.cvsm.2014.07.005","article-title":"Canine hereditary ataxia","volume":"44","author":"G Urkasemsin","year":"2014","journal-title":"Vet Clin North Am Small Anim Pract"},{"key":"pgen.1009716.ref007","unstructured":"OMIA\u2013Online Mendelian Inheritance in Animals [cited 2021 Jul06]. Available from: https:\/\/www.omia.org\/home\/"},{"key":"pgen.1009716.ref008","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/ejhg.2016.157","article-title":"The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME\/EAST homologue in Malinois dogs","volume":"25","author":"M Van Poucke","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"pgen.1009716.ref009","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1534\/g3.116.038455","article-title":"A missense variant in KCNJ10 in Belgian Shepherd Dogs affected by spongy degeneration with cerebellar ataxia (SDCA1).","volume":"7","author":"N Mauri","year":"2017","journal-title":"G3"},{"key":"pgen.1009716.ref010","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1534\/g3.117.043018","article-title":"A SINE insertion in ATP1B2 in Belgian Shepherd Dogs affected by spongy degeneration with cerebellar ataxia (SDCA2).","volume":"7","author":"N Mauri","year":"2017","journal-title":"G3"},{"key":"pgen.1009716.ref011","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3390\/genes11030313","article-title":"YARS2 missense variant in Belgian Shepherd Dogs with cardiomyopathy and juvenile mortality","volume":"11","author":"C Gurtner","year":"2020","journal-title":"Genes (Basel)."},{"key":"pgen.1009716.ref012","first-page":"17","article-title":"Z\u00e1chyt spinocerebel\u00e1rn\u00ed ataxie u ATP1B2 heterozygotn\u00edch Malinois \u0161t\u011b\u0148at: Kolik na\u0161ich chovn\u00fdch Belgick\u00fdch ov\u010d\u00e1k\u016f je p\u0159ena\u0161e\u010d\u016f neurodegenerativn\u00edch onemocn\u011bn\u00ed?","volume":"71","author":"P \u017d\u00e1kov\u00e1","year":"2021","journal-title":"Veterinarstvi."},{"key":"pgen.1009716.ref013","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1146\/annurev-nutr-071714-034250","article-title":"Regulation of selenium metabolism and transport","volume":"35","author":"RF Burk","year":"2015","journal-title":"Annu Rev Nutr"},{"key":"pgen.1009716.ref014","doi-asserted-by":"crossref","first-page":"630016","DOI":"10.3389\/fnins.2021.630016","article-title":"Selenium at the neural barriers: A review","volume":"15","author":"N Solovyev","year":"2021","journal-title":"Front Neurosci."},{"key":"pgen.1009716.ref015","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1042\/bj20021853","article-title":"Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues","volume":"370","author":"L Schomburg","year":"2003","journal-title":"Biochem J"},{"key":"pgen.1009716.ref016","doi-asserted-by":"crossref","first-page":"13640","DOI":"10.1074\/jbc.M300755200","article-title":"Deletion of selenoprotein P alters distribution of selenium in the mouse","volume":"278","author":"KE Hill","year":"2003","journal-title":"J Biol Chem"},{"key":"pgen.1009716.ref017","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/jn\/134.1.157","article-title":"Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene","volume":"134","author":"KE Hill","year":"2004","journal-title":"J Nutr"},{"key":"pgen.1009716.ref018","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1093\/jn\/137.3.690","article-title":"All regions of mouse brain are dependent on selenoprotein P for maintenance of selenium","volume":"137","author":"A Nakayama","year":"2007","journal-title":"J Nutr"},{"key":"pgen.1009716.ref019","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1126\/science.1083516","article-title":"Characterization of mammalian selenoproteomes","volume":"300","author":"GV Kryukov","year":"2003","journal-title":"Science"},{"key":"pgen.1009716.ref020","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1096\/fj.14-252874","article-title":"Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration","volume":"28","author":"RF Burk","year":"2014","journal-title":"FASEB J"},{"key":"pgen.1009716.ref021","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S0304-4165(00)00035-0","article-title":"Synthesis and secretion of selenoprotein P by cultured rat astrocytes","volume":"1474","author":"X Yang","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"pgen.1009716.ref022","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3390\/antiox8090357","article-title":"Selenocysteine \u03b2-Lyase: biochemistry, regulation and physiological role of the selenocysteine decomposition enzyme","volume":"8","author":"LA Seale","year":"2019","journal-title":"Antioxidants"},{"key":"pgen.1009716.ref023","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3233\/JPD-2012-11052","article-title":"Changes in selenoprotein P in substantia nigra and putamen in Parkinson\u2019s disease.","volume":"2","author":"FP Bellinger","year":"2012","journal-title":"J Parkinsons Dis"},{"key":"pgen.1009716.ref024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jinorgbio.2015.09.003","article-title":"Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signaling","volume":"153","author":"ND Solovyew","year":"2015","journal-title":"J Inorg Biochem"},{"key":"pgen.1009716.ref025","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1097\/NEN.0b013e318160f347","article-title":"Neurodegeneration in mice resulting from loss of functional selenoprotein P or its receptor apolipoprotein E receptor 2","volume":"67","author":"WM Valentine","year":"2008","journal-title":"J Neuropathol Exp Neurol"},{"key":"pgen.1009716.ref026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2011.04.046","article-title":"Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted","volume":"1398","author":"SW Caito","year":"2011","journal-title":"Brain Res"},{"key":"pgen.1009716.ref027","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s12011-014-9920-z","article-title":"Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons","volume":"158","author":"EK Wirth","year":"2014","journal-title":"Biol Trace Elem Res"},{"key":"pgen.1009716.ref028","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1212\/WNL.0000000000001787","article-title":"Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate","volume":"85","author":"AK Anttonen","year":"2015","journal-title":"Neurology"},{"key":"pgen.1009716.ref029","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"S Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"key":"pgen.1009716.ref030","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ng786","article-title":"Merlin\u2014rapid analysis of dense genetic maps using sparse gene flow trees","volume":"30","author":"GR Abecasis","year":"2002","journal-title":"Nat Genet"},{"key":"pgen.1009716.ref031","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/age.12834","article-title":"A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves","volume":"50","author":"V Jagannathan","year":"2019","journal-title":"Anim Genet"},{"key":"pgen.1009716.ref032","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"A McKenna","year":"2010","journal-title":"Genome Res"},{"key":"pgen.1009716.ref033","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1093\/nar\/gku1174","article-title":"DoGSD: the dog and wolf genome SNP database","volume":"43","author":"B Bai","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pgen.1009716.ref034","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff.","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)."}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1009716","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009716","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T19:24:16Z","timestamp":1628796256000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009716"}},"subtitle":[],"editor":[{"given":"Laurent","family":"Tiret","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,8,2]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1009716","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pgen.1009716","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,2]]}}}