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

ABSTRACT: 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 tRNAIle 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 tRNAIle We therefore hypothesized that the m.4317A?G mutation alters both structure and function of tRNAIle 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 tRNAIle These m.4317A?G mutation-induced alterations in tRNAIle structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555A?G mutation. Furthermore, mutant cell lines bearing both m.4317A?G and m.1555A?G 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.1555A?G mutation. Our findings provide new insights into the pathophysiology of maternally inherited deafness arising from the synergy between mitochondrial 12S rRNA and tRNA mutations.

SUBMITTER: Meng F 

PROVIDER: S-EPMC5836119 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature