Clarin-2 is essential for hearing by maintaining stereocilia integrity and function

Lucy A. Dunbar; Pranav Patni; Carlos Aguilar; Philomena Mburu; Laura Corns; Helena R.R. Wells; Sedigheh Delmaghani; Andrew Parker; Stuart Johnson; Debbie Williams; Christopher T. Esapa; Michelle M. Simon; Lauren Chessum; Sherylanne Newton; Joanne Dorning; Prashanthini Jeyarajan; Susan Morse; Andrea Lelli; Gemma F. Codner; Thibault Peineau; Suhasini R. Gopal; Kumar N. Alagramam; Ronna Hertzano; Didier Dulon; Sara Wells; Frances M. Williams; Christine Petit; Sally J. Dawson; Steve D.M. Brown; Walter Marcotti; Aziz El-Amraoui; Michael R. Bowl

doi:10.15252/emmm.201910288

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function

Lucy A. Dunbar, Pranav Patni, Carlos Aguilar, Philomena Mburu, Laura Corns, Helena R.R. Wells, Sedigheh Delmaghani, Andrew Parker, Stuart Johnson, Debbie Williams, Christopher T. Esapa, Michelle M. Simon, Lauren Chessum, Sherylanne Newton, Joanne Dorning, Prashanthini Jeyarajan, Susan Morse, Andrea Lelli, Gemma F. Codner, Thibault PeineauSuhasini R. Gopal, Kumar N. Alagramam, Ronna Hertzano, Didier Dulon, Sara Wells, Frances M. Williams, Christine Petit, Sally J. Dawson, Steve D.M. Brown, Walter Marcotti, Aziz El-Amraoui^*, Michael R. Bowl

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

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

15 Citations (Scopus)

Abstract

Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2^{clarinet/clarinet} mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

Original language	English
Article number	e10288
Journal	EMBO Molecular Medicine
Volume	11
Issue number	9
DOIs	https://doi.org/10.15252/emmm.201910288
Publication status	Published - 1 Sept 2019

Keywords

hair cells
mechanotransduction
mouse models
mutagenesis
stereocilia

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10.15252/emmm.201910288

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Dunbar, L. A., Patni, P., Aguilar, C., Mburu, P., Corns, L., Wells, H. R. R., Delmaghani, S., Parker, A., Johnson, S., Williams, D., Esapa, C. T., Simon, M. M., Chessum, L., Newton, S., Dorning, J., Jeyarajan, P., Morse, S., Lelli, A., Codner, G. F., ... Bowl, M. R. (2019). Clarin-2 is essential for hearing by maintaining stereocilia integrity and function. EMBO Molecular Medicine, 11(9), Article e10288. https://doi.org/10.15252/emmm.201910288

@article{df841bd6c68046ac94d59e6e81bca1e6,

title = "Clarin-2 is essential for hearing by maintaining stereocilia integrity and function",

abstract = "Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.",

keywords = "hair cells, mechanotransduction, mouse models, mutagenesis, stereocilia",

author = "Dunbar, {Lucy A.} and Pranav Patni and Carlos Aguilar and Philomena Mburu and Laura Corns and Wells, {Helena R.R.} and Sedigheh Delmaghani and Andrew Parker and Stuart Johnson and Debbie Williams and Esapa, {Christopher T.} and Simon, {Michelle M.} and Lauren Chessum and Sherylanne Newton and Joanne Dorning and Prashanthini Jeyarajan and Susan Morse and Andrea Lelli and Codner, {Gemma F.} and Thibault Peineau and Gopal, {Suhasini R.} and Alagramam, {Kumar N.} and Ronna Hertzano and Didier Dulon and Sara Wells and Williams, {Frances M.} and Christine Petit and Dawson, {Sally J.} and Brown, {Steve D.M.} and Walter Marcotti and Aziz El-Amraoui and Bowl, {Michael R.}",

year = "2019",

month = sep,

day = "1",

doi = "10.15252/emmm.201910288",

language = "English",

volume = "11",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

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Dunbar, LA, Patni, P, Aguilar, C, Mburu, P, Corns, L, Wells, HRR, Delmaghani, S, Parker, A, Johnson, S, Williams, D, Esapa, CT, Simon, MM, Chessum, L, Newton, S, Dorning, J, Jeyarajan, P, Morse, S, Lelli, A, Codner, GF, Peineau, T, Gopal, SR, Alagramam, KN, Hertzano, R, Dulon, D, Wells, S, Williams, FM, Petit, C, Dawson, SJ, Brown, SDM, Marcotti, W, El-Amraoui, A & Bowl, MR 2019, 'Clarin-2 is essential for hearing by maintaining stereocilia integrity and function', EMBO Molecular Medicine, vol. 11, no. 9, e10288. https://doi.org/10.15252/emmm.201910288

TY - JOUR

T1 - Clarin-2 is essential for hearing by maintaining stereocilia integrity and function

AU - Dunbar, Lucy A.

AU - Patni, Pranav

AU - Aguilar, Carlos

AU - Mburu, Philomena

AU - Corns, Laura

AU - Wells, Helena R.R.

AU - Delmaghani, Sedigheh

AU - Parker, Andrew

AU - Johnson, Stuart

AU - Williams, Debbie

AU - Esapa, Christopher T.

AU - Simon, Michelle M.

AU - Chessum, Lauren

AU - Newton, Sherylanne

AU - Dorning, Joanne

AU - Jeyarajan, Prashanthini

AU - Morse, Susan

AU - Lelli, Andrea

AU - Codner, Gemma F.

AU - Peineau, Thibault

AU - Gopal, Suhasini R.

AU - Alagramam, Kumar N.

AU - Hertzano, Ronna

AU - Dulon, Didier

AU - Wells, Sara

AU - Williams, Frances M.

AU - Petit, Christine

AU - Dawson, Sally J.

AU - Brown, Steve D.M.

AU - Marcotti, Walter

AU - El-Amraoui, Aziz

AU - Bowl, Michael R.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

AB - Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

KW - hair cells

KW - mechanotransduction

KW - mouse models

KW - mutagenesis

KW - stereocilia

UR - http://www.scopus.com/inward/record.url?scp=85071788636&partnerID=8YFLogxK

U2 - 10.15252/emmm.201910288

DO - 10.15252/emmm.201910288

M3 - Article

C2 - 31448880

AN - SCOPUS:85071788636

SN - 1757-4676

VL - 11

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 9

M1 - e10288

ER -

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function

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Keywords

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