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- 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.
- Authors
Pingping Jiang; Xiaofen Jin; Yanyan Peng; Meng Wang; Hao Liu; Xiaoling Liu; Zengjun Zhang; Yanchun Ji; Juanjuan Zhang; Min Liang; Fuxin Zhao; Yan-Hong Sun; Minglian Zhang; Xiangtian Zhou; Ye Chen; Jun Qin Mo; Taosheng Huang; Jia Qu; Min-Xin Guan
- Abstract
Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclearmodifier 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-RNA 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>Valmutations) and controls lacking these mutations. The 191Gly>Valmutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNATyr 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 tRNATyr 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.
- Publication
Human Molecular Genetics, 2016, Vol 25, Issue 3, p584
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddv498