@article{a102e0dc089b4c62bd0f7d1550d742d5,
title = "A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder",
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.",
keywords = "Auditory neuropathy spectrum disorder, Cochlea, Connexins, Glia-like supporting cells",
author = "Jang, {Minwoo Wendy} and Oh, {Doo Yi} and Eunyoung Yi and Xuezhong Liu and Jie Ling and Nayoung Kim and Kushal Sharma and Kim, {Tai Young} and Seungmin Lee and Kim, {Ah Reum} and Kim, {Min Young} and Kim, {Min A.} and Mingyu Lee and Han, {Jin Hee} and Han, {Jae Joon} and Park, {Hye Rim} and Kim, {Bong Jik} and Lee, {Sang Yeon} and Woo, {Dong Ho} and Jayoung Oh and Oh, {Soo Jin} and Tingting Du and Koo, {Ja Won} and Oh, {Seung Ha} and Shin, {Hyun Woo} and Seong, {Moon Woo} and Lee, {Kyu Yup} and Kim, {Un Kyung} and Shin, {Jung Bum} and Shushan Sang and Xinzhang Cai and Lingyun Mei and Chufeng He and Blanton, {Susan H.} and Chen, {Zheng Yi} and Hongsheng Chen and Xianlin Liu and Aida Nourbakhsh and Zaohua Huang and Kang, {Kwon Woo} and Park, {Woong Yang} and Yong Feng and {Justin Lee}, C. and Choi, {Byung Yoon}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Young-Woo Seo at Korea Basic Science Institute Gwang-Ju Center for his assistance with image analysis with Imaris software. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (Grant HI15C1632 and HI17C0952 to B.Y.C.); the Creative Research Initiative Program, National Research Foundation of Korea (NRF) (Grant 2015R1A3A2066619 to C.J.L.); Grant IBS-R001-D2 from the Institute for Basic Science from the Ministry of Science (to C.J.L.); the Basic Science Research Program through the NRF, funded by the Ministry of Education (Grant 2019R1I1A3A01063625 to E.Y.); the National Natural Science Foundation of China (Grants 82071065 and 81771023 to Y.F.); and the Major State Basic Research Development Program of China (973 Program) (Grant 2014CB541702 to Y.F.). Xuezhong Liu is supported by NIH Grants R01DC005575, R01DC012115, and A.N. is supported by NIH Grant T32 DC015995. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = jun,
day = "1",
doi = "10.1073/pnas.2019681118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "22",
}