The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells
In: EMBO Molecular Medicine EMBO Molecular Medicine, 2014, 6 (7), pp.984-92. ⟨10.15252/emmm.201403976⟩ EMBO Molecular Medicine, Wiley Open Access, 2014, 6 (7), pp.984-92. ⟨10.15252/emmm.201403976⟩ EMBO molecular medicine Publons; (2014-06-17)
Online
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Zugriff:
International audience; Protocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cyto-plasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15 ex38-fl/ex38-fl Myo15-cre +/À) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical trans-duction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.
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The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells
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| Autor/in / Beteiligte Person: | Goodyear, Richard J. ; Dupont, Typhaine ; Makrelouf, Mohamed ; Avan, Paul ; Hardelin, Jean-Pierre ; Holder, Muriel ; Pepermans, Elise ; Bahloul, Amel ; Gherbi, Souad ; Abdi, Samia ; Michel, Vincent ; Petit, Christine ; Marlin, Sandrine ; Richardson, Guy P. ; Zenati, Akila ; Bonnet, Crystel ; Collège de France - Chaire Génétique et physiologie cellulaire ; Collège de France (CdF (institution)) ; School of Life Sciences ; University of Sussex ; Syndrome de Usher et autres atteintes rétino-cochléaires ; Institut de la Vision ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Génétique et Biologie ; Université Saâd Dahlab Blida 1 (UB1)- Centre Hospitalo-Universitaire de Blida (CHU Blida) ; Centre de référence des Surdités Génétiques [CHU Necker, Paris] ; CHU Necker - Enfants Malades [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Service de Génétique clinique ; Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille) ; Laboratoire de Biochimie Génétique ; CHU de Bab El Oued-Université d'Alger 1 ; Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP) ; UNICANCER ; (Neuro-Dol), Neuro-Dol ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]) ; Equipe Biophysique Neurosensorielle [Neuro-Dol] ; Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; EP wassupported by a fellowship from the Fondation Raymonde et Guy Strittmatter.This work was supported by ERC-Hair bundle (ERC-2011-ADG_294570), FoundationBNP Paribas and LHW-Stiftung to CP ; Tassili project funding to CP andAZ and Wellcome Trust programme grant (WT087377) to GR. This workperformed in the frame of the LABEX LIFESENSES [reference ANR-10-LABX-65]was supported by French state funds managed by the ANR within the Investissementsd’Avenir programme under reference ANR-11-IDEX-0004-02. ; ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011) ; European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012) ; Chaire Génétique et physiologie cellulaire ; Université de Saâd Dahlab [Blida] (USDB )- Centre Hospitalo-Universitaire de Blida (CHU Blida) ; Centre de référence des Surdités Génétiques ; Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX -, VALID ; Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 -, VALID |
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| Quelle: | EMBO Molecular Medicine EMBO Molecular Medicine, 2014, 6 (7), pp.984-92. ⟨10.15252/emmm.201403976⟩ EMBO Molecular Medicine, Wiley Open Access, 2014, 6 (7), pp.984-92. ⟨10.15252/emmm.201403976⟩ EMBO molecular medicine Publons; (2014-06-17) |
| Veröffentlichung: | HAL CCSD, 2014 |
| Medientyp: | unknown |
| ISSN: | 1757-4676 (print) ; 1757-4684 (print) |
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