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Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in <jats:italic>IARS2<\/jats:italic> have been reported to cause LS. However, the pathogenic mechanism of <jats:italic>IARS2<\/jats:italic> variants is still unclear.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and <jats:italic>IARS2<\/jats:italic>-knockdown HEK293T cells to evaluate the pathogenicity of the variants.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We reported 2 unrelated Chinese patients manifested with LS who carried biallelic <jats:italic>IARS2<\/jats:italic> variants (c.1_390del and c.2450G\u2009&gt;\u2009A from a 4-year-old boy, and c.2090G\u2009&gt;\u2009A and c.2122G\u2009&gt;\u2009A from a 5-year-old boy), of which c.1_390del and c.2090G\u2009&gt;\u2009A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G\u2009&gt;\u2009A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in <jats:italic>IARS2<\/jats:italic>-knockdown HEK293T cells. The compensatory experiments in <jats:italic>vitro<\/jats:italic> cell models confirmed the pathogenicity of <jats:italic>IARS2<\/jats:italic> variants since re-expression of wild-type <jats:italic>IARS2<\/jats:italic> rather than mutant <jats:italic>IARS2<\/jats:italic> could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in <jats:italic>IARS2<\/jats:italic> knockdown cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of <jats:italic>IARS2<\/jats:italic> variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of <jats:italic>IARS2<\/jats:italic> mutation-related diseases.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03310-x","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T09:00:46Z","timestamp":1724403646000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency"],"prefix":"10.1186","volume":"19","author":[{"given":"Qiyu","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuanglong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keer","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Refiloe Laurentinah","family":"Mahlatsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxin","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hezhi","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6229-4495","authenticated-orcid":false,"given":"Ya","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"issue":"4","key":"3310_CR1","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1002\/ana.26313","volume":"91","author":"SL Stenton","year":"2022","unstructured":"Stenton SL, Zou Y, Cheng H, Liu Z, Wang J, Shen D, Jin H, Ding C, Tang X, Sun S. 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