Jang, Minwoo Wendy Oh, Doo-Yi Yi, Eunyoung Liu, Xuezhong Ling, Jie Kim, Nayoung Sharma, Kushal Kim, Tai Young 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 Seung-Ha Oh 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 Lee, C. Justin Choi, Byung Yoon 2024-01-19T14:31:41Z 2024-01-19T14:31:41Z 2021-10-21 2021-06-01 0027-8424 https://pubs.kist.re.kr/handle/201004/116873 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. English NATL ACAD SCIENCES AUDITORY NEUROPATHY GAP-JUNCTIONS HEARING IMPAIRMENT SUPPORTING CELLS HAIR-CELLS MUTATIONS DEAFNESS DIFFERENTIATION GUIDELINES MECHANISM A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant disorder Article 10.1073/pnas.2019681118 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.118, no.22 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118 22 scie scopus 000659433500008 2-s2.0-85107205166 Multidisciplinary Sciences Science & Technology - Other Topics Article AUDITORY NEUROPATHY GAP-JUNCTIONS HEARING IMPAIRMENT SUPPORTING CELLS HAIR-CELLS MUTATIONS DEAFNESS DIFFERENTIATION GUIDELINES MECHANISM auditory neuropathy spectrum disorder cochlea glia-like supporting cells connexins