오두이 (분당서울대학교병원) | 한빛사논문 > 한빛사

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오두이Doo-Yi Oh

분당서울대학교병원

Proc. Natl. Acad. Sci. USA, June 1, 2021, 118 (22) : e2019681118 | https://doi.org/10.1073/pnas.2019681118 A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

Minwoo Wendy Jang^a,b,1, Doo-Yi Oh^c,1, Eunyoung Yi^d,1, Xuezhong Liu^e,f,1, Jie Ling^g,h,1, Nayoung Kimⁱ, Kushal Sharma^d, Tai Young Kim^b, Seungmin Lee^c, Ah-Reum Kim^c, Min Young Kim^c, Min-A Kim^j,k, Mingyu Lee^l, Jin-Hee Han^c, Jae Joon Han^m, Hye-Rim Park^c, Bong Jik Kim^c, Sang-Yeon Lee^m, Dong Ho Wooⁿ, Jayoung Oh^c, Soo-Jin Oh^o, Tingting Du^p, Ja-Won Koo^c, Seung-Ha Oh^m, Hyun-Woo Shin^m, Moon-Woo Seong^q, Kyu-Yup Lee^r, Un-Kyung Kim^j,k, Jung Bum Shin^p, Shushan Sang^g, Xinzhang Cai^g, Lingyun Mei^g, Chufeng He^g, Susan H. Blanton^e,f, Zheng-Yi Chen^s, Hongsheng Chen^g, Xianlin Liu^g, Aida Nourbakhsh^e, Zaohua Huang^e, Kwon-Woo Kang^d, Woong-Yang Parkⁱ, Yong Feng^g,t,2, C. Justin Lee^a,b,2, and Byung Yoon Choi^c,2

^aKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; ^bCenter for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Republic of Korea; ^cDepartment of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea; ^dCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea; ^eDepartment of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136; ^fDr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; ^gDepartment of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; ^hInstitute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; ⁱSamsung Medical Center, Samsung Genome Institute, Seoul 06351, Republic of Korea; ^jDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; ^kSchool of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu 41566, Republic of Korea; ^lDepartment of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea; ^mDepartment of Otorhinolaryngology, Seoul National University Hospital, Seoul 03080, Republic of Korea; ⁿResearch Center for Animal Model, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea; ^oConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; ^pDepartment of Neuroscience, University of Virginia, Charlottesville, VA 22908; ^qDepartment of Laboratory Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea; ^rDepartment of Otorhinolaryngology-Head and Neck Surgery, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; ^sDepartment of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Boston, MA 02114; and ^tDepartment of Otolaryngology, University of South China Affiliated Changsha Central Hospital, Changsha, Hunan 410004, China

¹M.W.J., D.-Y.O., E.Y., X.L., and J.L. contributed equally to this work.
²To whom correspondence may be addressed.

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.

auditory neuropathy spectrum disorder, cochlea, glia-like supporting cells, connexins

논문정보

형식Research article
게재일2021년 06월 (BRIC 등록일 2021-06-03)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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