Contribution of the tRNAIle 4317A→G mutation to the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA 1555A→G mutation

作者：Feilong Meng, Zheyun He, Xiaowen Tang, Jing Zheng, Xiaofen Jin, Yi Zhu, Xiaoyan Ren, Mi Zhou, Meng Wang, Shasha Gong, Jun Qin Mo, Qiang Shu, Min‐Xin Guan · 发表于：Journal of Biological Chemistry · 年份：2018 · DOI：10.1074/jbc.ra117.000530 · 被引用次数：41 · 研究领域：Mitochondrial Function and Pathology、RNA and protein synthesis mechanisms、ATP Synthase and ATPases Research

The 1555A→G mutation in mitochondrial 12S rRNA has been associated with aminoglycoside-induced and non-syndromic deafness in many individuals worldwide. Mitochondrial genetic modifiers are proposed to influence the phenotypic expression of m.1555A→G mutation. Here, we report that a deafness-susceptibility allele (m.4317A→G) in the tRNA Ile gene modulates the phenotype expression of m.1555A→G mutation. Strikingly, a large Han Chinese pedigree carrying both m.4317A→G and m.1555A→G mutations exhibited much higher penetrance of deafness than those carrying only the m.1555A→G mutation. The m.4317A→G mutation affected a highly conserved adenine at position 59 in the T-loop of tRNA Ile . We therefore hypothesized that the m.4317A→G mutation alters both structure and function of tRNA Ile . Using lymphoblastoid cell lines derived from members of Chinese families (three carrying both m.1555A→G and m.4317A→G mutations, three harboring only m.1555A→G mutation, and three controls lacking these mutations), we found that the cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited more severe mitochondrial dysfunctions than those carrying only the m.1555A→G mutation. We also found that the m.4317A→G mutation perturbed the conformation, stability, and aminoacylation efficiency of tRNA Ile . These m.4317A→G mutation-induced alterations in tRNA Ile structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555A→G mutat...