Mutational analysis of mitochondrial tRNA genes in 138 patients with Leber's hereditary optic neuropathy

Introduction Mutations in mitochondrial DNA (mtDNA) are the most important causes for Leber's hereditary optic neuropathy (LHON). Of these, three primary mtDNA mutations account for more than 90% cases of this disease. However, to date, little is known regarding the relationship between mitochondrial tRNA (mt-tRNA) variants and LHON. Aim In this study, we aimed to investigate the association between mt-tRNA variants and LHON. Methodology One hundred thirty-eight LHON patients lacking three primary mutations (ND1 3460G > A, ND4 11778Gxs > A, and ND6 14484 T > C), as well as 266 controls were enrolled in this study. PCR-Sanger sequencing was performed to screen the mt-tRNA variants. Moreover, the phylogenetic analysis, pathogenicity scoring system, as well as mitochondrial functions were performed. Results We identified 8 possible pathogenic variants: tRNA(Phe) 593 T > C, tRNA(Leu(UUR)) 3275C > T, tRNA(Gln) 4363 T > C, tRNA(Met) 4435A > G, tRNA(Ala) 5587 T > C, tRNA(Glu) 14693A > G, tRNA(Thr) 15927G > A, and 15951A > G, which may change the structural and functional impact on the corresponding tRNAs, and subsequently lead to a failure in tRNA metabolism. Furthermore, significant reductions in mitochondrial ATP and MMP levels and an overproduction of ROS were observed in cybrid cells containing these mt-tRNA variants, suggesting that these variants may lead to mitochondrial dysfunction which was responsible for LHON. Conclusion Our study indicated that mt-tRNA variants were associated with LHON, and screening for mt-tRNA variants were recommended for early detection, diagnosis, and prevention of maternally inherited LHON.

Automated summary

This study identified 8 possible pathogenic mt-tRNA variants associated with LHON, which may impact tRNA metabolism and lead to mitochondrial dysfunction. Significant reductions in mitochondrial ATP and MMP levels, as well as an overproduction of ROS, were observed in cells containing these variants, suggesting their potential role in the development of LHON. Screening for mt-tRNA variants is recommended for early detection, diagnosis, and prevention of maternally inherited LHON.