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인지 및 사회성 연구단
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A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

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Title
A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder
Author(s)
CCS; Oh, Doo-Yi; Yi, Eunyoung; Liu, Xuezhong; Ling, Jie; Kim, Nayoung; Sharma, Kushal; Tai Young Kim; Lee, Seungmin; Kim, Ah-Reum; Kim, Min Young; Kim, Min-A; Lee, Mingyu; Han, Jin-Hee; Han, Jae Joon; Park, Hye-Rim; Kim, Bong Jik; Lee, Sang-Yeon; Woo, Dong Ho; Oh, Jayoung; Oh, Soo-Jin; Du, Tingting; Koo, Ja-Won; Oh, Seung-Ha; Shin, Hyun-Woo; Seong, Moon-Woo; Lee, Kyu-Yup; Kim, Un-Kyung; Shin, Jung Bum; Sang, Shushan; Cai, Xinzhang; Mei, Lingyun; He, Chufeng; Blanton, Susan H.; Chen, Zheng-Yi; Chen, Hongsheng; Liu, Xianlin; Nourbakhsh, Aida; Huang, Zaohua; Kang, Kwon-Woo; Park, Woong-Yang; Feng, Yong; C. Justin Lee; Choi, Byung Yoon
Publication Date
2021-06
Journal
Proceedings of the National Academy of Sciences of the United States of America, v.118, no.22
Publisher
National Academy of Sciences
Abstract
© 2021 National Academy of Sciences. All rights reserved.Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.
URI
https://pr.ibs.re.kr/handle/8788114/9880
DOI
10.1073/pnas.2019681118
ISSN
0027-8424
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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