{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T04:09:08Z","timestamp":1768968548378,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T00:00:00Z","timestamp":1765670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"3billion, Inc., \u201c2nd End the Diagnostic Odyssey Grant\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MLASA2 is a rare mitochondrial disorder with limited geographic representation in published medical literature. Here, we report the first confirmed case of MLASA2 in a Latin American 16-year-old male harboring a homozygous pathogenic variant p.(Asp311Glu) in the YARS2 gene. The patient presented with sideroblastic anemia and short stature, accompanied by other skeletal dysplasia features not previously associated with MLASA2, including epiphyseal dysplasia, rib edge widening, and poorly defined vertebral structures, but without lactic acidosis. Notably, the patient did not present exercise intolerance but recently exhibited reduced muscle strength. The p.(Asp311Glu) variant, located in the anticodon-binding domain of the mitochondrial tyrosyl-tRNA synthetase (Mt-TyrRS), was consistently predicted to be pathogenic by multiple in silico tools. Molecular modeling revealed that this variant destabilizes the \u2018KMSKS\u2019 motif, potentially compromising tRNA recognition fidelity and aminoacylation efficiency. Analysis of runs of homozygosity (ROH) revealed significantly elevated consanguinity (ROH: 31.93%), consistent with a consanguineous mating between biological parents. This case expands the geographic distribution of MLASA2, documents previously unreported phenotypes, suggests a novel pathogenic mechanism, and demonstrates the utility of genomic approaches for diagnosing rare mitochondrial disorders in the absence of complete clinical information and family history.<\/jats:p>","DOI":"10.3390\/ijms262412039","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:36:39Z","timestamp":1765791399000},"page":"12039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First Latin American Case of MLASA2 Caused by a Pathogenic Variant in the Anticodon-Binding Domain of YARS2"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6135-4270","authenticated-orcid":false,"given":"Jos\u00e9 Rafael","family":"Villaf\u00e1n-Bernal","sequence":"first","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"},{"name":"Programa de Investigadoras e Investigadores por M\u00e9xico, Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n, Mexico City 03940, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jhonatan","family":"Rosas-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro de Rehabilitaci\u00f3n Infantil Telet\u00f3n, Altamira 89607, Tamaulipas, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0453-980X","authenticated-orcid":false,"given":"Humberto","family":"Garc\u00eda-Ortiz","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9883-2988","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"Mart\u00ednez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7994-3831","authenticated-orcid":false,"given":"Cecilia","family":"Contreras-Cubas","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4956-5921","authenticated-orcid":false,"given":"Israel","family":"Guerrero-Contreras","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4736-0412","authenticated-orcid":false,"given":"Hane","family":"Lee","sequence":"additional","affiliation":[{"name":"3billion, Inc., Seoul 03161, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-1791","authenticated-orcid":false,"given":"Go Hun","family":"Seo","sequence":"additional","affiliation":[{"name":"3billion, Inc., Seoul 03161, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4511-4557","authenticated-orcid":false,"given":"Alessandra","family":"Carnevale","sequence":"additional","affiliation":[{"name":"Mendelian Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5064-6203","authenticated-orcid":false,"given":"Francisco","family":"Barajas-Olmos","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5801-9180","authenticated-orcid":false,"given":"Lorena","family":"Orozco","sequence":"additional","affiliation":[{"name":"Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Gen\u00f3mica, Secretar\u00eda de Salud, Mexico City 14610, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"ref_1","unstructured":"McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (2025, October 21). Myopathy, Lactic Acidosis, and Sideroblastic Anemia 2; MLASA2\u2014Entry\u2014# 613561 OMIM. Available online: https:\/\/www.omim.org\/entry\/613561."},{"key":"ref_2","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--MLASA Syndrome","volume":"87","author":"Riley","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1001\/jamaneurol.2016.4357","article-title":"Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy","volume":"74","author":"Sommerville","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"e564","DOI":"10.3324\/haematol.2018.194464","article-title":"Sideroblastic Anemia with Myopathy Secondary to Novel, Pathogenic Missense Variants in the YARS2 Gene","volume":"103","author":"Smith","year":"2018","journal-title":"Haematologica"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1002\/ajmg.a.62755","article-title":"Decompensation of Cardiorespiratory Function and Emergence of Anemia during Pregnancy in a Case of Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia 2 with Compound Heterozygous YARS2 Pathogenic Variants","volume":"188","author":"Rudaks","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","first-page":"95","article-title":"A Novel Homozygous YARS2 Mutation in Two Italian Siblings and a Review of Literature","volume":"20","author":"Ardissone","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-386497-0.00001-3","article-title":"Quality Control in Aminoacyl-TRNA Synthesis Its Role in Translational Fidelity","volume":"86","author":"Yadavalli","year":"2012","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101123","DOI":"10.1016\/j.isci.2020.101123","article-title":"Rare Genetic Diseases: Nature\u2019s Experiments on Human Development","volume":"23","author":"Lee","year":"2020","journal-title":"iScience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/ajmg.1320550325","article-title":"Myopathy, Lactic Acidosis, and Sideroblastic Anemia: A New Syndrome","volume":"55","author":"Inbal","year":"1995","journal-title":"Am. J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1083\/jcb.201809056","article-title":"Respiratory Chain Inactivation Links Cartilage-Mediated Growth Retardation to Mitochondrial Diseases","volume":"218","author":"Holzer","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_12","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":"161A","author":"Shahni","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e202502205","DOI":"10.1083\/jcb.202502205","article-title":"Mechanisms of genome instability from cellular folate stress","volume":"224","author":"Mellor","year":"2025","journal-title":"J Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev.nutr.24.012003.132306","article-title":"New insights into erythropoiesis: The roles of folate, vitamin B12, and iron","volume":"24","author":"Koury","year":"2004","journal-title":"Annu. Rev. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1002\/pbc.25981","article-title":"Study of Glycine and Folic Acid Supplementation to Ameliorate Transfusion Dependence in Congenital SLC25A38 Mutated Sideroblastic Anemia","volume":"63","author":"LeBlanc","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1056\/NEJM199403103301004","article-title":"X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevulinate synthase","volume":"330","author":"Cox","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ymgme.2013.04.007","article-title":"Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation","volume":"109","author":"Wen","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2326409817707771","DOI":"10.1177\/2326409817707771","article-title":"Coenzyme Q10 in the Treatment of Mitochondrial Disease","volume":"5","author":"Neergheen","year":"2017","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1056\/NEJMoa051469","article-title":"Genetic modifiers of lung disease in cystic fibrosis","volume":"353","author":"Drumm","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mueller, E.E., Brunner, S.M., Mayr, J.A., Stanger, O., Sperl, W., and Kofler, B. (2012). Functional differences between mitochondrial haplogroup T and haplogroup H in HEK293 cybrid cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052367"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.bbadis.2012.04.014","article-title":"Oxidative phosphorylation differences between mitochondrial DNA haplogroups modify the risk of Leber\u2019s hereditary optic neuropathy","volume":"1822","author":"Montoya","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33426","DOI":"10.1074\/jbc.274.47.33426","article-title":"Threshold effect and tissue specificity. Implication for mitochondrial cytopathies","volume":"274","author":"Rossignol","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/gim.2012.94","article-title":"Regions of Homozygosity Identified by SNP Microarray Analysis Aid in the Diagnosis of Autosomal Recessive Disease and Incidentally Detect Parental Blood Relationships","volume":"15","author":"Sund","year":"2013","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5942","DOI":"10.1038\/s41467-021-26188-w","article-title":"The Genomic Landscape of Mexican Indigenous Populations Brings Insights into the Peopling of the Americas","volume":"12","author":"Baca","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Turvey, A.K., Horvath, G.A., and Cavalcanti, A.R.O. (2022). Aminoacyl-tRNA synthetases in human health and disease. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.1029218"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1002\/cphg.93","article-title":"Overview of Specifications to the ACMG\/AMP Variant Interpretation Guidelines","volume":"103","author":"Harrison","year":"2019","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41525-024-00455-3","article-title":"Exome Sequencing of 18,994 Ethnically Diverse Patients with Suspected Rare Mendelian Disorders","volume":"10","author":"Han","year":"2025","journal-title":"NPJ Genom. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/cge.13848","article-title":"Diagnostic Yield and Clinical Utility of Whole Exome Sequencing Using an Automated Variant Prioritization System, EVIDENCE","volume":"98","author":"Seo","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41586-019-1231-2","article-title":"Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls","volume":"570","author":"Flannick","year":"2019","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12039\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:46:04Z","timestamp":1765791964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,14]]},"references-count":30,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262412039"],"URL":"https:\/\/doi.org\/10.3390\/ijms262412039","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,14]]}}}