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

EMBO Molecular Medicine

Laura Corns¹  Stuart Johnson¹  Walter Marcotti¹  Kumar N Alagramam²  Suhasini R Gopal²  Ronna Hertzano³  Helena RR Wells⁴  Frances M Williams⁴  Sedigheh Delmaghani⁵  Aziz El‐Amraoui⁵  Pranav Patni⁵  Christine Petit⁶  Andrea Lelli⁶  Thibault Peineau⁷  Didier Dulon⁷  Carlos Aguilar⁸  Prashanthini Jeyarajan⁸  Philomena Mburu⁸  Michael R Bowl⁸  Christopher T Esapa⁸  Lauren Chessum⁸  Susan Morse⁸  Joanne Dorning⁸  Michelle M Simon⁸  Andrew Parker⁸  Lucy A Dunbar⁸  Debbie Williams⁸  Steve DM Brown⁸  Sherylanne Newton⁸  Gemma F Codner⁹  Sara Wells⁹  Sally J Dawson^1,10 

[1] Department of Biomedical Science University of Sheffield Sheffield UK;Department of Otolaryngology – Head and Neck Surgery University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USA;Department of Otorhinolaryngology Head and Neck Surgery, Anatomy and Neurobiology and Institute for Genome Sciences University of Maryland School of Medicine Baltimore MD USA;Department of Twin Research & Genetic Epidemiology King's College London London UK;Déficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris France;Génétique et Physiologie de l'Audition Institut Pasteur INSERM UMR‐S 1120 Collège de France Sorbonne Universités Paris France;Laboratoire de Neurophysiologie de la Synapse Auditive Université de Bordeaux Bordeaux France;Mammalian Genetics Unit MRC Harwell Institute Harwell UK;Mary Lyon Centre MRC Harwell Institute Harwell UK;UCL Ear Institute University College London London UK;

关键词: hair cells;    mechanotransduction;    mouse models;    mutagenesis;    stereocilia;   

DOI  :  10.15252/emmm.201910288

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown