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dc.contributor.authorDunbar, L.A.
dc.contributor.authorPatni, P.
dc.contributor.authorHertzano, R.
dc.date.accessioned2019-09-16T15:13:00Z
dc.date.available2019-09-16T15:13:00Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85071788636&doi=10.15252%2femmm.201910288&partnerID=40&md5=4e39d85d894899f62e248f973f95de78
dc.identifier.urihttp://hdl.handle.net/10713/10852
dc.description.abstractHearing 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. Copyright 2019 The Authors.en_US
dc.description.sponsorshipThis work was supported by: Medical Research Council (MC_U142684175 to S.D.M.B. and MC_UP_1503/2 to M.R.B), Wellcome Trust (102892 to W.M.); the French National Research Agency (ANR) as part of the second “Investissements d'Avenir” programme (light4deaf, ANR‐15‐RHUS‐0001) and LHW‐Stiftung (to C.P. & A.E.); ANR‐HearInNoise‐(ANR‐17‐CE16‐0017 to A.E.); NIDCD/NIH (R01DC013817), NIMH/NIH (R24MH114815) and the Hearing Restoration Program of the Hearing Health Foundation (to R.H.); and an Action on Hearing Loss PhD studentship (to F.W. and S.Da.), which was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. L.D. is a Medical Research Council PhD student. P.P. benefited from a fellowship from the European Union's Horizon 2020 Marie Sklodowska‐Curie grant No 665807. S.L.J. is a Royal Society University Research Fellow.en_US
dc.description.urihttps://doi.org/10.15252/emmm.201910288en_US
dc.language.isoen-USen_US
dc.publisherBlackwell Publishing Ltden_US
dc.relation.ispartofEMBO Molecular Medicine
dc.subjecthair cellsen_US
dc.subjectmechanotransductionen_US
dc.subjectmouse modelsen_US
dc.subjectmutagenesisen_US
dc.subjectstereociliaen_US
dc.titleClarin-2 is essential for hearing by maintaining stereocilia integrity and functionen_US
dc.typeArticleen_US
dc.identifier.doi10.15252/emmm.201910288
dc.identifier.pmid31448880


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