Department of Ophthalmology, the Affiliated Hospital of Nantong University, Nantong, China.
Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China.
Ir J Med Sci. 2022 Apr;191(2):865-876. doi: 10.1007/s11845-021-02656-6. Epub 2021 May 29.
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.
In this study, we aimed to investigate the association between mt-tRNA variants and LHON.
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.
We identified 8 possible pathogenic variants: tRNA 593 T > C, tRNA 3275C > T, tRNA 4363 T > C, tRNA 4435A > G, tRNA 5587 T > C, tRNA 14693A > G, tRNA 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.
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.
线粒体 DNA（mtDNA）突变是 Leber 遗传性视神经病变（LHON）的最重要原因。其中，三种主要的 mtDNA 突变占该病 90%以上的病例。然而，迄今为止，对于线粒体 tRNA（mt-tRNA）变体与 LHON 之间的关系知之甚少。
本研究旨在探讨 mt-tRNA 变体与 LHON 的关系。
本研究纳入了 138 例缺乏三种主要突变（ND1 3460G>A、ND4 11778Gxs>A 和 ND6 14484T>C）的 LHON 患者和 266 例对照者。采用 PCR-Sanger 测序法筛查 mt-tRNA 变体。此外，还进行了系统发育分析、致病性评分系统以及线粒体功能分析。
我们发现了 8 种可能的致病性变体：tRNA 593T>C、tRNA 3275C>T、tRNA 4363T>C、tRNA 4435A>G、tRNA 5587T>C、tRNA 14693A>G、tRNA 15927G>A 和 15951A>G，这些变体可能改变相应 tRNA 的结构和功能，进而导致 tRNA 代谢失败。此外，在含有这些 mt-tRNA 变体的细胞系中观察到线粒体 ATP 和 MMP 水平显著降低以及 ROS 过度产生，提示这些变体可能导致线粒体功能障碍，这是 LHON 的原因。
本研究表明 mt-tRNA 变体与 LHON 相关，建议筛查 mt-tRNA 变体，以实现对母系遗传 LHON 的早期检测、诊断和预防。
