{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T23:07:39Z","timestamp":1768950459276,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Myopathy, Lactic Acidosis, and Sideroblastic Anemia type 2 (MLASA2) is a rare mitochondrial disorder caused by pathogenic variants (PVs) in the YARS2 gene (which encodes the Mt-TyrRS protein. We performed a comprehensive clinical\u2013molecular synthesis by integrating a systematic review and meta-analysis of all published MLASA2 cases with survival modeling and three-dimensional structural mapping. Across the aggregated cohort, anemia (88.6%), sideroblastic phenotype (85.7%), and lactic acidosis (82.9%) were the most prevalent phenotypes. Fifteen PVs were identified, dominated by p.(Phe52Leu) (29.4%). Survival estimates were 94.1% at 10 years, 70.7% at 30 years, and 42.4% at 50 years; cardiomyopathy and diagnosis before age 10 were associated with decreased survival. We generated the first 3D structural map of all reported Mt-TyrRS PVs, identifying nine spatial hotspots across catalytic, anticodon-binding, and tRNA-binding domains. An integrated framework combining structural density, clinical severity, in silico predictions, and \u0394\u0394G destabilization classified three clusters as High-risk, three as Medium-risk, and three as Low-risk. Among them, cluster 3, a large catalytic hotspot encompassing 44 residues and including nearly half of all MLASA2 cases, showed the strongest pathogenic convergence. This clinical\u2013structural integration provides new insights for a better comprehension of MLASA2, enhancing variant interpretation and improving diagnostic and prognostic precision.<\/jats:p>","DOI":"10.3390\/cimb48010095","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"95","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Correlation of MLASA2 Clinical Phenotype and Survival with Mt-TyrRS Protein Damage: Linking Systematic Review, Meta-Analysis and 3D Hotspot Mapping"],"prefix":"10.3390","volume":"48","author":[{"given":"Jos\u00e9 Rafael","family":"Villafan-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":"Investigador por M\u00e9xico, Secretar\u00eda de Humanidades Ciencia, Tecnolog\u00eda e Innovaci\u00f3n, Mexico City 03940, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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\/0000-0002-0453-980X","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\/0000-0002-7994-3831","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"}]},{"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"}]},{"given":"Jos\u00e9 Luis","family":"Fr\u00edas-Cabrera","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\/0000-0002-3512-4519","authenticated-orcid":false,"given":"Federico","family":"Centeno-Cruz","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\/0000-0003-3989-1798","authenticated-orcid":false,"given":"Monserrat Ivonne","family":"Morales Rivera","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"}]},{"given":"Jhonatan Rosas","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro de Rehabilitaci\u00f3n Infantil, Telet\u00f3n, Altamira 89607, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"}]},{"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":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/ped.12217","article-title":"Pathophysiology and Genetic Mutations in Congenital Sideroblastic Anemia","volume":"55","author":"Fujiwara","year":"2013","journal-title":"Pediatr. 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