| Title: | Clarin-2 is essential for hearing by maintaining stereocilia integrity and function |
| Journal: | EMBO Molecular Medicine |
| Published: | 26 Aug 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31448880/ |
| DOI: | https://doi.org/10.15252/emmm.201910288 |
| Citations: | 21 (3 in last 2 years) as of 8 Aug 2024 |
Publication 4512
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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.</p>
32 Authors
- 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
Enabling scientific discoveries that improve human health