[No authors listed]
The 1555AâG 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.1555AâG mutation. Here, we report that a deafness-susceptibility allele (m.4317AâG) in the tRNAIle gene modulates the phenotype expression of m.1555AâG mutation. Strikingly, a large Han Chinese pedigree carrying both m.4317AâG and m.1555AâG mutations exhibited much higher penetrance of deafness than those carrying only the m.1555AâG mutation. The m.4317AâG mutation affected a highly conserved adenine at position 59 in the T-loop of tRNAIle We therefore hypothesized that the m.4317AâG mutation alters both structure and function of tRNAIle Using lymphoblastoid cell lines derived from members of Chinese families (three carrying both m.1555AâG and m.4317AâG mutations, three harboring only m.1555AâG mutation, and three controls lacking these mutations), we found that the cell lines bearing both m.4317AâG and m.1555AâG mutations exhibited more severe mitochondrial dysfunctions than those carrying only the m.1555AâG mutation. We also found that the m.4317AâG mutation perturbed the conformation, stability, and aminoacylation efficiency of tRNAIle These m.4317AâG mutation-induced alterations in tRNAIle structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555AâG mutation. Furthermore, mutant cell lines bearing both m.4317AâG and m.1555AâG mutations exhibited greater reductions in the mitochondrial ATP levels and membrane potentials and increasing production of reactive oxygen species than those carrying only the m.1555AâG mutation. Our findings provide new insights into the pathophysiology of maternally inherited deafness arising from the synergy between mitochondrial 12S rRNA and tRNA mutations.
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