Zhao LJ, Zhang ZL, Fu Y. Novel m.4268T>C mutation in the mitochondrial tRNAIle gene is associated with hearing loss in two Chinese families. World J Clin Cases 2022; 10(1): 205-216 [PMID: 35071519 DOI: 10.12998/wjcc.v10.i1.205]
Corresponding Author of This Article
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
Research Domain of This Article
Otorhinolaryngology
Article-Type of This Article
Observational Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
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
Abstract
BACKGROUND
Herein, we report the genetic, clinical, molecular and biochemical features of two Han Chinese pedigrees with suggested maternally transmitted non-syndromic hearing loss.
AIM
To investigate the pathophysiology of hearing loss associated with mitochondrial tRNA mutations.
METHODS
Sixteen subjects from two Chinese families with hearing loss underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of tRNA levels using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects.
RESULTS
Three of the 16 matrilineal relatives in these families exhibited a variable seriousness and age-at-onset (8 years) of deafness. Analysis of mtDNA mutation identified the novel homoplasmic tRNAIle 4268T>C mutation in two families both belonging to haplogroup D4j. The 4268T>C mutation is located in a highly conserved base pairing (6U–67A) of tRNAIle. The elimination of 6U–67A base-pairing may change the tRNAIle metabolism. Functional mutation was supported by an approximately 64.6% reduction in the level of tRNAIle observed in the lymphoblastoid cell lines with the 4268T>C mutation, in contrast to the wild-type cell lines. The reduced level of tRNA was below the proposed threshold for normal respiration in lymphoblastoid cells. However, genotyping analysis did not detect any mutations in the prominent deafness-causing gene GJB2 in any members of the family.
CONCLUSION
These data show that the novel tRNAIle 4268T>C mutation was involved in maternally transmitted deafness. However, epigenetic, other genetic, or environmental factors may be attributed to the phenotypic variability. These findings will be useful for understanding families with maternally inherited deafness.
Core Tip: The 4268T>C mutation is located in a relatively highly conserved base-pairing (6U–67A) of tRNAIle. The elimination of 6U–67A base-pairing may change tRNAIle metabolism. Moreover, the reduced tRNA level is inferior to the proposed threshold to maintain normal respiration in lymphoblastoid cells.
