EMBO Molecular Medicine (Sep 2019)
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function
- Lucy A Dunbar,
- Pranav Patni,
- Carlos Aguilar,
- Philomena Mburu,
- Laura Corns,
- Helena RR 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 DM Brown,
- Walter Marcotti,
- Aziz El‐Amraoui,
- Michael R Bowl
Affiliations
- Lucy A Dunbar
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Pranav Patni
- Déficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris France
- Carlos Aguilar
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Philomena Mburu
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Laura Corns
- Department of Biomedical Science University of Sheffield Sheffield UK
- Helena RR Wells
- Department of Twin Research & Genetic Epidemiology King's College London London UK
- Sedigheh Delmaghani
- Déficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris France
- Andrew Parker
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Stuart Johnson
- Department of Biomedical Science University of Sheffield Sheffield UK
- Debbie Williams
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Christopher T Esapa
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Michelle M Simon
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Lauren Chessum
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Sherylanne Newton
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Joanne Dorning
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Prashanthini Jeyarajan
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Susan Morse
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Andrea Lelli
- Génétique et Physiologie de l'Audition Institut Pasteur INSERM UMR‐S 1120 Collège de France Sorbonne Universités Paris France
- Gemma F Codner
- Mary Lyon Centre MRC Harwell Institute Harwell UK
- Thibault Peineau
- Laboratoire de Neurophysiologie de la Synapse Auditive Université de Bordeaux Bordeaux France
- Suhasini R Gopal
- Department of Otolaryngology – Head and Neck Surgery University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USA
- Kumar N Alagramam
- Department of Otolaryngology – Head and Neck Surgery University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USA
- Ronna Hertzano
- Department of Otorhinolaryngology Head and Neck Surgery, Anatomy and Neurobiology and Institute for Genome Sciences University of Maryland School of Medicine Baltimore MD USA
- Didier Dulon
- Laboratoire de Neurophysiologie de la Synapse Auditive Université de Bordeaux Bordeaux France
- Sara Wells
- Mary Lyon Centre MRC Harwell Institute Harwell UK
- Frances M Williams
- Department of Twin Research & Genetic Epidemiology King's College London London UK
- Christine Petit
- Génétique et Physiologie de l'Audition Institut Pasteur INSERM UMR‐S 1120 Collège de France Sorbonne Universités Paris France
- Sally J Dawson
- UCL Ear Institute University College London London UK
- Steve DM Brown
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- Walter Marcotti
- Department of Biomedical Science University of Sheffield Sheffield UK
- Aziz El‐Amraoui
- Déficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris France
- Michael R Bowl
- Mammalian Genetics Unit MRC Harwell Institute Harwell UK
- DOI
- https://doi.org/10.15252/emmm.201910288
- Journal volume & issue
-
Vol. 11,
no. 9
pp. n/a – n/a
Abstract
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