title: The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.
abstract: Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Jin
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Zengjun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, Hebei, China and.
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Rady Children's Hospital, University of California School of Medicine, San Diego, CA, USA.
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: Institute of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China, gminxin88@zju.edu.cn.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D029242:Optic Atrophy, Hereditary, Leber / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C098483:NADH dehydrogenase subunit 4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C481838:MT-ND5 protein, human; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D014448:Tyrosine-tRNA Ligase; D042967:Electron Transport Complex I