2. Academic Validation
  3. A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

  • Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):e2019681118. doi: 10.1073/pnas.2019681118.
Minwoo Wendy Jang 1 2,  Doo-Yi Oh 3,  Eunyoung Yi 4,  Xuezhong Liu 5 6,  Jie Ling 7 8,  Nayoung Kim 9,  Kushal Sharma 4,  Tai Young Kim 2,  Seungmin Lee 3,  Ah-Reum Kim 3,  Min Young Kim 3,  Min-A Kim 10 11,  Mingyu Lee 12,  Jin-Hee Han 3,  Jae Joon Han 13,  Hye-Rim Park 3,  Bong Jik Kim 3,  Sang-Yeon Lee 13,  Dong Ho Woo 14,  Jayoung Oh 3,  Soo-Jin Oh 15,  Tingting Du 16,  Ja-Won Koo 3,  Seung-Ha Oh 13,  Hyun-Woo Shin 13,  Moon-Woo Seong 17,  Kyu-Yup Lee 18,  Un-Kyung Kim 10 11,  Jung Bum Shin 16,  Shushan Sang 7,  Xinzhang Cai 7,  Lingyun Mei 7,  Chufeng He 7,  Susan H Blanton 5 6,  Zheng-Yi Chen 19,  Hongsheng Chen 7,  Xianlin Liu 7,  Aida Nourbakhsh 5,  Zaohua Huang 5,  Kwon-Woo Kang 4,  Woong-Yang Park 9,  Yong Feng 20 21,  C Justin Lee 22 2,  Byung Yoon Choi 23
Affiliations

Affiliations

  • 1 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
  • 2 Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Republic of Korea.
  • 3 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
  • 4 College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea.
  • 5 Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136.
  • 6 Dr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136.
  • 7 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 8 Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 9 Samsung Medical Center, Samsung Genome Institute, Seoul 06351, Republic of Korea.
  • 10 Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
  • 11 School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu 41566, Republic of Korea.
  • 12 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea.
  • 13 Department of Otorhinolaryngology, Seoul National University Hospital, Seoul 03080, Republic of Korea.
  • 14 Research Center for Animal Model, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea.
  • 15 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 16 Department of Neuroscience, University of Virginia, Charlottesville, VA 22908.
  • 17 Department of Laboratory Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
  • 18 Department of Otorhinolaryngology-Head and Neck Surgery, Kyungpook National University Hospital, Daegu 41944, Republic of Korea.
  • 19 Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Boston, MA 02114.
  • 20 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; fengyong_hn@hotmail.com cjl@ibs.re.kr choiby2010@gmail.com.
  • 21 Department of Otolaryngology, University of South China Affiliated Changsha Central Hospital, Changsha, Hunan 410004, China.
  • 22 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; fengyong_hn@hotmail.com cjl@ibs.re.kr choiby2010@gmail.com.
  • 23 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea; fengyong_hn@hotmail.com cjl@ibs.re.kr choiby2010@gmail.com.
PMID: 34050020 DOI: 10.1073/pnas.2019681118
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.

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