线粒体tRNA变异与听力损失之间的关联：一项病例对照研究。
The Association Between Mitochondrial tRNA Variants and Hearing Loss: A Case-Control Study.
作者信息
Yu Xuejiao, Li Sheng, Guo Qinxian, Leng Jianhang, Ding Yu
机构信息
Department of Clinical Laboratory, Quzhou People's Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, Zhejiang Province, 324000, People's Republic of China.
Department of Otolaryngology, Quzhou People's Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, Zhejiang Province, 324000, People's Republic of China.
出版信息
Pharmgenomics Pers Med. 2024 Mar 28;17:77-89. doi: 10.2147/PGPM.S441281. eCollection 2024.
PURPOSE
This study aimed to examine the frequencies of mt-tRNA variants in 180 pediatric patients with non-syndromic hearing loss (NSHL) and 100 controls.
METHODS
Sanger sequencing was performed to screen for mt-tRNA variants. These mitochondrial DNA (mtDNA) pathogenic mutations were further assessed using phylogenetic conservation and haplogroup analyses. We also traced the origins of the family history of probands carrying potential pathogenic mtDNA mutations. Mitochondrial functions including mtDNA content, ATP and reactive oxygen species (ROS) were examined in cells derived from patients carrying the mt-tRNA A14692G and CO1/tRNA G7444A variants and controls.
RESULTS
We identified four possible pathogenic variants: m.T14709C, m.A14683G, m.A14692G and m.A14693G, which were found in NSHL patients but not in controls. Genetic counseling suggested that one child with the m.A14692G variant had a family history of NSHL. Sequence analysis of mtDNA suggested the presence of the CO1/tRNA G7444A and mt-tRNA A14692G variants. Molecular analysis suggested that, compared with the controls, patients with these variants exhibited much lower mtDNA copy numbers, ATP production, whereas ROS levels increased (<0.05 for all), suggesting that the m.A14692G and m.G7444A variants led to mitochondrial dysfunction.
CONCLUSION
mt-tRNA variants are important risk factors for NSHL.
目的
本研究旨在检测180例非综合征性听力损失（NSHL）儿科患者和100例对照者中线粒体tRNA（mt-tRNA）变体的频率。
方法
采用桑格测序法筛选mt-tRNA变体。使用系统发育保守性和单倍群分析进一步评估这些线粒体DNA（mtDNA）致病突变。我们还追溯了携带潜在致病mtDNA突变的先证者家族史的起源。在携带mt-tRNA A14692G和CO1/tRNA G7444A变体的患者及对照者来源的细胞中检测了包括mtDNA含量、ATP和活性氧（ROS）在内的线粒体功能。
结果
我们鉴定出四种可能的致病变体：m.T14709C、m.A14683G、m.A14692G和m.A14693G，这些变体在NSHL患者中发现，而在对照者中未发现。遗传咨询表明，一名携带m.A14692G变体的儿童有NSHL家族史。mtDNA序列分析提示存在CO1/tRNA G7444A和mt-tRNA A14692G变体。分子分析表明，与对照者相比，携带这些变体的患者mtDNA拷贝数、ATP产生量低得多，而ROS水平升高（均P<0.05），提示m.A14692G和m.G7444A变体导致线粒体功能障碍。
结论
mt-tRNA变体是NSHL的重要危险因素。
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