A nonsense <i>TMEM43</i> 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 Oh, Soo‐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
Abstract
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.