{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FARS2 encodes the mitochondrial phenylalanyl–tRNA synthetase, a pivotal enzyme responsible for charging mitochondrial tRNAPhe with phenylalanine—a critical step for mitochondrial protein synthesis and proper assembly of the oxidative phosphorylation system. Structural and biochemical studies have shown that human mtPheRS is a compact, monomeric enzyme comprised of a catalytic module complemented by accessory domains inherited from ancestral bacterial counterparts, ensuring accurate ATP binding and substrate recognition. Pathogenic mutations in FARS2 impair its aminoacylation activity by disrupting ATP binding, reducing substrate affinity, and compromising protein stability; these defects lead to a decreased capacity for tRNA charging. In patients, such molecular dysfunction underlies a spectrum of mitochondrial disorders that manifest as early‐onset epileptic encephalopathy, spastic paraplegia, and other neurodegenerative phenotypes. Collectively, these findings highlight that proper FARS2 function is essential for mitochondrial translation and that its disruption directly contributes to mitochondrial disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jenni M Elo, Srujana S Yadavalli, Liliya Euro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/dds294"}], "href": "https://doi.org/10.1093/hmg/dds294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22833457"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22833457"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ying Yang, Wei Liu, Zhipeng Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.22930"}], "href": "https://doi.org/10.1002/humu.22930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26553276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26553276"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Elise Vantroys, Austin Larson, Marisa Friederich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New insights into the phenotype of FARS2 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2017.10.004"}], "href": "https://doi.org/10.1016/j.ymgme.2017.10.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29126765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29126765"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hilary J Vernon, Rebecca McClellan, Denise A S Batista, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.36993"}], "href": "https://doi.org/10.1002/ajmg.a.36993"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25851414"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25851414"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mohammed Almannai, Julia Wang, Hongzheng Dai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2018.07.014"}], "href": "https://doi.org/10.1016/j.ymgme.2018.07.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30177229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30177229"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Inna Levin, Naama Kessler, Nina Moor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Purification, crystallization and preliminary X-ray characterization of a human mitochondrial phenylalanyl-tRNA synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr Sect F Struct Biol Cryst Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/S1744309107038651"}], "href": "https://doi.org/10.1107/S1744309107038651"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17768348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17768348"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shruti Chakraborty, Michael Ibba, Rajat Banerjee "}, {"type": "b", "children": [{"type": "t", "text": "Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl-tRNA synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "IUBMB Life (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/iub.2114"}], "href": "https://doi.org/10.1002/iub.2114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31241862"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31241862"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ekaterine Kartvelishvili, Dmitry Tworowski, Hilary Vernon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pro.3176"}], "href": "https://doi.org/10.1002/pro.3176"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28419689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28419689"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Giulia Barcia, Marlène Rio, Zahra Assouline, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-020-00757-x"}], "href": "https://doi.org/10.1038/s41431-020-00757-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33168986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33168986"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Federico Raviglione, Giorgio Conte, Daniele Ghezzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical findings in a patient with FARS2 mutations and early-infantile-encephalopathy with epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.37836"}], "href": "https://doi.org/10.1002/ajmg.a.37836"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27549011"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27549011"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Srujana S Yadavalli, Liron Klipcan, Alexey Zozulya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Large-scale movement of functional domains facilitates aminoacylation by human mitochondrial phenylalanyl-tRNA synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2009.09.008"}], "href": "https://doi.org/10.1016/j.febslet.2009.09.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19737557"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19737557"}]}]}]}