A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder.
Minwoo Wendy JangDoo-Yi OhEunyoung YiXuezhong LiuJie LingNayoung KimKushal SharmaTai Young KimSeungmin LeeAh-Reum KimMin Young KimMin-A KimMingyu LeeJin-Hee HanJae Joon HanHye-Rim ParkBong Jik KimSang-Yeon LeeDong Ho WooJayoung OhSoo-Jin OhTingting DuJa-Won KooSeung-Ha OhHyun-Woo ShinMoon-Woo SeongKyu-Yup LeeUn-Kyung KimJung Bum ShinShushan SangXinzhang CaiLingyun MeiChufeng HeSusan Halloran BlantonZheng-Yi ChenHongsheng ChenXianlin LiuAida NourbakhshZaohua HuangKwon-Woo KangWoong-Yang ParkYong FengJustin Daho LeeByung Yoon ChoiPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.