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

Minwoo Wendy Jang, Doo Yi Oh, Eunyoung Yi, Xuezhong Liu, Jie Ling, Nayoung Kim, Kushal Sharma, Tai Young Kim, Seungmin Lee, Ah Reum Kim, Min Young Kim, Min A. Kim, Mingyu Lee, Jin Hee Han, Jae Joon Han, Hye Rim Park, Bong Jik Kim, Sang Yeon Lee, Dong Ho Woo, Jayoung OhSoo Jin Oh, Tingting Du, Ja Won Koo, Seung Ha Oh, Hyun Woo Shin, Moon Woo Seong, Kyu Yup Lee, Un Kyung Kim, Jung Bum Shin, Shushan Sang, Xinzhang Cai, Lingyun Mei, Chufeng He, Susan H. Blanton, Zheng Yi Chen, Hongsheng Chen, Xianlin Liu, Aida Nourbakhsh, Zaohua Huang, Kwon Woo Kang, Woong Yang Park, Yong Feng, C. Justin Lee, Byung Yoon Choi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere2019681118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number22
DOIs
StatePublished - Jun 1 2021
Externally publishedYes

Keywords

  • Auditory neuropathy spectrum disorder
  • Cochlea
  • Connexins
  • Glia-like supporting cells

ASJC Scopus subject areas

  • General

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