Observational Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jan 7, 2022; 10(1): 205-216
Published online Jan 7, 2022. doi: 10.12998/wjcc.v10.i1.205
Novel m.4268T>C mutation in the mitochondrial tRNAIle gene is associated with hearing loss in two Chinese families
Li-Jing Zhao, Zhi-Li Zhang, Yong Fu
Li-Jing Zhao, Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Zhi-Li Zhang, Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Yong Fu, Department of Otorhinolaryngology Head and Neck Surgery, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Author contributions: Fu Y designed the study; Zhao LJ and Zhang ZL acquired and analyzed the data; Fu Y wrote the article; all authors reviewed and approved the final version to be published.
Institutional review board statement: Informed consent, blood samples, and clinical evaluations were obtained from all participants and family members according to protocols approved by the Ethics Committee of Zhejiang University School of Medicine.
Informed consent statement: All study participants or their legal guardian provided informed written consent regarding personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: The authors have no conflict of interest related to the manuscript.
Data sharing statement: The original anonymous dataset is available on request from the corresponding author at 1307022@zju.edu.cn.
STROBE statement: The guidelines of the STROBE Statement have been adopted.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yong Fu, MD, Doctor, Department of Otorhinolaryngology Head and Neck Surgery, The Children’s Hospital, Zhejiang University School of Medicine, No. 57 Zhugan Lane, Xiacheng District, Hangzhou 310009, Zhejiang Province, China. 1307022@zju.edu.cn
Received: June 17, 2021
Peer-review started: June 17, 2021
First decision: July 16, 2021
Revised: July 23, 2021
Accepted: November 29, 2021
Article in press: November 29, 2021
Published online: January 7, 2022
Processing time: 195 Days and 18.3 Hours
ARTICLE HIGHLIGHTS

We identified the novel homoplasmic tRNAIle 4268T>C mutation in two families, which was located at a highly conserved base-pairing (6U–67A) of tRNAIle. The abolishment of 6U–67A base-pairing likely changes tRNAIle metabolism. Moreover, the proposed threshold of normal respiration in lymphoblastoid cells was more than the reduced tRNA level.

Research background

Mutations in mitochondrial rRNA and tRNA genes have been identified as one of the most common reasons for sensorineural hearing loss. In this investigation, two Han Chinese pedigrees with maternally transmitted non-syndromic deafness were studied and the clinical, molecular and genetic characterization was investigated, which suggested maternally transmitted non-syndromic hearing impairment.

Research motivation

In the present study, two Han Chinese pedigrees with maternally transmitted non-syndromic deafness were studied and the clinical, molecular and genetic characterization was investigated. Mutational analysis of the entire mtDNA identified the novel homoplasmic tRNAIle 4268T>C mutation, which disrupts a highly conservative base-pairing (6U–67A) on the ACC stem of tRNAIle. The steady-state levels of mitochondrial tRNA were detected with cybrid cell lines for functional significance of the 4268T>C mutation.

Research objectives

To investigate the pathophysiology of hearing loss associated with mitochondrial tRNA mutations.

Research methods

Sixteen subjects from two Chinese families with deafness were assessed using clinical, genetic, molecular, and biochemical techniques. We measured the tRNA levels in lymphoblastoid cell lines derived from three control subjects and five affected matrilineal relatives of the families.

Research results

Variable severity and age-at-onset (8 years) of deafness were exhibited by three of the 16 matrilineal relatives from the families. The novel homoplasmic tRNAIle 4268T>C mutation was identified by mutational analysis of mtDNA in two families that belonged to haplogroup D4j. The base-pairing (6U–67A) of tRNAIle was a highly conserved gene where the 4268T>C mutation was located. The metabolism of tRNAIle could be changed by the abolishment of 6U–67A base-pairing. Compared with the wild-type cell lines, the lymphoblastoid cell lines with the 4268T>C mutation were observed at the level of tRNAIle with an approximately 64.6% reduction. Normal respiration in lymphoblastoid cells requires a higher threshold level than this reduced tRNA level. However, genotyping analysis did not detect any mutations in the prominent deafness-causing gene GJB2 in any members from the family.

Research conclusions

The novel tRNAIle 4268T>C mutation may lead to maternally transmitted deafness. However, the phenotypic variability in the family may also be derived from epigenetic, other genetic, or environmental factors. These results may be of value in counseling, especially for families with maternally inherited deafness.

Research perspectives

Future molecular diagnosis of deafness can include the tRNAIle 4268T>C mutation as one of the inherited risk factors. Thus, the results may have important value in deafness counseling, especially for families with maternally inherited deafness.