{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:23:20Z","timestamp":1768983800057,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,14]],"date-time":"2020-03-14T00:00:00Z","timestamp":1584144000000},"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>Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G&gt;A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G&gt;A as the candidate causative variant for the observed juvenile mortality.<\/jats:p>","DOI":"10.3390\/genes11030313","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T10:01:35Z","timestamp":1584612095000},"page":"313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality"],"prefix":"10.3390","volume":"11","author":[{"given":"Corinne","family":"Gurtner","sequence":"first","affiliation":[{"name":"Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Hug","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Kleiter","sequence":"additional","affiliation":[{"name":"Department\/Hospital for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kernt","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Pathology, Justus-Liebig-University Giessen, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-6083","authenticated-orcid":false,"given":"Elisabeth","family":"Dietschi","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1751-0147-49-S1-S2","article-title":"Canine neonatal mortality in four large breeds","volume":"49","author":"Trangerud","year":"2007","journal-title":"Acta Vet. Scand."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/rda.12845","article-title":"Reproductive performance and pre-weaning mortality: Preliminary analysis of 27,221 purebred female dogs and 204,537 puppies in France","volume":"52","author":"Guillemot","year":"2017","journal-title":"Reprod. Dom. Anim."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/rda.12329","article-title":"Causes, diagnosis and therapy of common diseases in neonatal puppies in the first days of life: Cornerstones of practical approach","volume":"49","year":"2014","journal-title":"Reprod. Dom. Anim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.theriogenology.2019.07.027","article-title":"Incidence of congenital malformations and impact on the mortality of neonatal canines","volume":"140","author":"Bernardo","year":"2019","journal-title":"Theriogenology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vetmic.2011.09.007","article-title":"Canine parvovirus\u2014A review of epidemiological and diagnostic aspects, with emphasis on type 2c","volume":"155","author":"Decaro","year":"2012","journal-title":"Vet. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13028-014-0092-9","article-title":"Prevalence of canid herpesvirus-1 infection in stillborn and dead neonatal puppies in Denmark","volume":"57","author":"Larsen","year":"2015","journal-title":"Acta Vet. Scand."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1136\/vr.142.22.602","article-title":"Investigation of mortality and pathological changes in a 14-month birth cohort of boxer puppies","volume":"142","author":"Nielen","year":"1998","journal-title":"Vet. Rec."},{"key":"ref_8","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":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","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":"Abecasis","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_10","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":"Jagannathan","year":"2019","journal-title":"Anim. Genet."},{"key":"ref_11","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: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_12","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":"Bai","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/s41467-019-09373-w","article-title":"Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology","volume":"10","author":"Plassais","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"W222","DOI":"10.1093\/nar\/gkx313","article-title":"PMut: A web-based tool for the annotation of pathological variants on proteins, 2017 update","volume":"45","author":"Gazzo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1016\/j.str.2007.09.018","article-title":"Crystal structure of human mitochondrial tyrosyl-tRNA synthetase reveals common and idiosyncratic features","volume":"15","author":"Bonnefond","year":"2007","journal-title":"Structure"},{"key":"ref_17","unstructured":"(2019, December 17). PDB Entry 2PID\u2014Crystal Structure of Human Mitochondrial Tyrosyl-tRNA Synthetase in Complex with an Adenylate Analog. Available online: http:\/\/www.rcsb.org\/pdb\/results\/results.do?tabtoshow=Current&qrid=D9008E42."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1093\/emboj\/cdf373","article-title":"Class I tyrosyl-tRNA synthetase has a class II mode of cognate tRNA recognition","volume":"21","author":"Yaremchuk","year":"2002","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/1873-3468.12962","article-title":"The role of tRNA synthetases in neurological and neuromuscular disorders","volume":"592","author":"Boczonadi","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ajhg.2010.06.001","article-title":"Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia\u2014MLASA syndrome","volume":"87","author":"Riley","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/1750-1172-8-193","article-title":"Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia","volume":"8","author":"Riley","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/jhg.2013.143","article-title":"A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2","volume":"59","author":"Nakajima","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1002\/humu.22098","article-title":"A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia","volume":"8","author":"Sasarman","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1002\/ajmg.a.36065","article-title":"A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations","volume":"9","author":"Shahni","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.3324\/haematol.2017.182659","article-title":"The phenotypic spectrum of germline YARS2 variants: From isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2","volume":"103","author":"Riley","year":"2018","journal-title":"Haematologica"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hadji Rasouliha, S., Barrientos, L., Anderegg, L., Klesty, C., Lorenz, J., Chevallier, L., Jagannathan, V., R\u00f6sch, S., and Leeb, T. (2019). A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs. 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