Gao Zhen, Yuan Ya-Sheng
Department of Otology and Skull Base Surgery, Eye & ENT Hospital.
NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China.
Medicine (Baltimore). 2020 Mar;99(13):e19373. doi: 10.1097/MD.0000000000019373.
Mutations in mitochondrial DNA, especially in 12S rRNA gene, are the most important causes for hearing loss. In particular, the A1555G and C1494T mutations have been found to be associated with both aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. To determine the frequency of C1494T mutation in deaf patients, in the current study, we screened this mutation in 655 patients with non-syndromic hearing loss and 300 control subjects. After PCR amplification of mitochondrial 12S rRNA gene and direct sequence analysis, we found that there were 2 patients carrying the C1494T mutation; however, this mutation was not detected in 300 healthy subjects. Further genetic counseling suggested that only 1 patient had an obvious family history of hearing impairment. Clinical evaluation showed that 3 of 10 matrilineal relatives suffered from hearing loss, with different age at onset of hearing loss. Molecular analysis revealed the presence of homoplasmic 12S rRNA C1494T and ND5 T12338C mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup F2. Interestingly, T12338C mutation resulted in the replacement of the first amino acid, a translation-initiating methionine with a threonine, shortening 2 amino acids of ND5 polypeptide. Moreover, this mutation is located in 2 nucleotides adjacent to the 3' end of the mt-tRNALeu(CUN) gene. Therefore, this mutation may alter ND5 mRNA metabolism and the processing of RNA precursors. Thus, the combination of T12338C and C1494T mutations may contribute to deafness expression in this family. Taken together, our data suggested that the C1494T mutation was the molecular basis for hearing loss, screening for the mitochondrial DNA pathogenic mutations was recommended for early detection, prevention, and diagnosis of mitochondrial deafness.
线粒体DNA突变，尤其是12S rRNA基因的突变，是听力损失的最重要原因。特别是，已发现在全球许多家族中，A1555G和C1494T突变与氨基糖苷类药物诱发的和非综合征性听力损失均相关。为了确定聋患者中C1494T突变的频率，在本研究中，我们在655例非综合征性听力损失患者和300例对照受试者中筛查了该突变。通过线粒体12S rRNA基因的PCR扩增和直接序列分析，我们发现有2例患者携带C1494T突变；然而，在300例健康受试者中未检测到该突变。进一步的遗传咨询表明，只有1例患者有明显的听力障碍家族史。临床评估显示，10名母系亲属中有3人患有听力损失，听力损失的发病年龄不同。分子分析揭示了同质性的12S rRNA C1494T和ND5 T12338C突变的存在，以及一组属于人类线粒体单倍群F2的多态性。有趣的是，T12338C突变导致第一个氨基酸，即翻译起始甲硫氨酸被苏氨酸取代，使ND5多肽缩短了2个氨基酸。此外，该突变位于mt-tRNALeu(CUN)基因3'端相邻的2个核苷酸处。因此，该突变可能会改变ND5 mRNA代谢和RNA前体的加工。因此，T12338C和C1494T突变的组合可能导致该家族的耳聋表现。综上所述，我们的数据表明C1494T突变是听力损失的分子基础，建议筛查线粒体DNA致病突变以早期检测、预防和诊断线粒体耳聋。
