A nonsense TMEM43 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

doi: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, 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 OhSoo 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

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24 Scopus citations

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.

Original language	English
Article number	e2019681118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	22
DOIs	https://doi.org/10.1073/pnas.2019681118
State	Published - 1 Jun 2021

Keywords

Auditory neuropathy spectrum disorder
Cochlea
Connexins
Glia-like supporting cells

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10.1073/pnas.2019681118

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Jang, M. W., Oh, D. Y., Yi, E., Liu, X., Ling, J., Kim, N., Sharma, K., Kim, T. Y., Lee, S., Kim, A. R., Kim, M. Y., Kim, M. A., Lee, M., Han, J. H., Han, J. J., Park, H. R., Kim, B. J., Lee, S. Y., Woo, D. H., ... Choi, B. Y. (2021). A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proceedings of the National Academy of Sciences of the United States of America, 118(22), Article e2019681118. https://doi.org/10.1073/pnas.2019681118

@article{9117eaa5a73a42a08bbe61672951047d,

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}",

year = "2021",

month = jun,

day = "1",

doi = "10.1073/pnas.2019681118",

language = "English",

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",

}

Jang, MW, Oh, DY, Yi, E, Liu, X, Ling, J, Kim, N, Sharma, K, Kim, TY, Lee, S, Kim, AR, Kim, MY, Kim, MA, Lee, M, Han, JH, Han, JJ, Park, HR, Kim, BJ, Lee, SY, Woo, DH, Oh, J, Oh, SJ, Du, T, Koo, JW, Oh, SH, Shin, HW, Seong, MW, Lee, KY, Kim, UK, Shin, JB, Sang, S, Cai, X, Mei, L, He, C, Blanton, SH, Chen, ZY, Chen, H, Liu, X, Nourbakhsh, A, Huang, Z, Kang, KW, Park, WY, Feng, Y, Justin Lee, C & Choi, BY 2021, 'A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 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. / Jang, Minwoo Wendy; Oh, Doo Yi; Yi, Eunyoung et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 22, e2019681118, 01.06.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

AU - Jang, Minwoo Wendy

AU - Oh, Doo Yi

AU - Yi, Eunyoung

AU - Liu, Xuezhong

AU - Ling, Jie

AU - Kim, Nayoung

AU - Sharma, Kushal

AU - Kim, Tai Young

AU - Lee, Seungmin

AU - Kim, Ah Reum

AU - Kim, Min Young

AU - Kim, Min A.

AU - Lee, Mingyu

AU - Han, Jin Hee

AU - Han, Jae Joon

AU - Park, Hye Rim

AU - Kim, Bong Jik

AU - Lee, Sang Yeon

AU - Woo, Dong Ho

AU - Oh, Jayoung

AU - Oh, Soo Jin

AU - Du, Tingting

AU - Koo, Ja Won

AU - Oh, Seung Ha

AU - Shin, Hyun Woo

AU - Seong, Moon Woo

AU - Lee, Kyu Yup

AU - Kim, Un Kyung

AU - Shin, Jung Bum

AU - Sang, Shushan

AU - Cai, Xinzhang

AU - Mei, Lingyun

AU - He, Chufeng

AU - Blanton, Susan H.

AU - Chen, Zheng Yi

AU - Chen, Hongsheng

AU - Liu, Xianlin

AU - Nourbakhsh, Aida

AU - Huang, Zaohua

AU - Kang, Kwon Woo

AU - Park, Woong Yang

AU - Feng, Yong

AU - Justin Lee, C.

AU - Choi, Byung Yoon

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

KW - Auditory neuropathy spectrum disorder

KW - Cochlea

KW - Connexins

KW - Glia-like supporting cells

UR - http://www.scopus.com/inward/record.url?scp=85107205166&partnerID=8YFLogxK

U2 - 10.1073/pnas.2019681118

DO - 10.1073/pnas.2019681118

M3 - Article

C2 - 34050020

AN - SCOPUS:85107205166

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 22

M1 - e2019681118

ER -

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

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Keywords

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