The CD2 isoform of protocadherin‐15 is an essential component of the tip‐link complex in mature auditory hair cells

EMBO Molecular Medicine

Elise Pepermans³  Vincent Michel³  Richard Goodyear¹  Crystel Bonnet⁸  Samia Abdi⁷  Typhaine Dupont³  Souad Gherbi⁵  Muriel Holder⁴  Mohamed Makrelouf⁶  Jean-Pierre Hardelin³  Sandrine Marlin⁵  Akila Zenati⁶  Guy Richardson¹  Paul Avan²  Amel Bahloul³ 

[1] School of Life Sciences, University of Sussex, Brighton, UK;Laboratoire de Biophysique Sensorielle, Université d'Auvergne, Clermont-Ferrand, France;Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France;Service de Génétique Clinique, Hôpital Jeanne-de-Flandre, Lille, France;Centre de référence des Surdités Génétiques, Hôpital Necker, Paris, France;Laboratoire de Biochimie Génétique, Université d'Alger 1, Alger, Algérie;Centre Hospitalier universitaire de Blida, Université Saad Dahleb, Blida, Algérie;UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

关键词: auditory mechano‐electrical transduction;    deafness;    protocadherin‐15;    stereocilia;    tip‐link;   

DOI  :  10.15252/emmm.201403976

来源: Wiley

【 摘 要 】

Abstract

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 cytoplasmic 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^+/−) 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 transduction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.

Synopsis

Pcdh15-CD2 isoform is shown essential for auditory function in mature hair cells both in humans and mice but not for visual function and make the lower part of the tip-link in inner ears. This is a major advance for the development of gene therapy for deafness caused by PCDH15 defects.

• In immature mouse cochlear hair cells, the three protocadherin-15 splice isoforms (CD1, CD2 and CD3), which differ only by their cytoplasmic region, are redundant to form the lower part of the tip-links, fibrous link that gate the mechano-electrical transduction channels.
• In contrast, the CD2 isoform is an indispensable tip-link component in mature mouse cochlear hair cells.
• The CD2 isoform of protocadherin-15 is also mandatory for hearing in humans as revealed by the identification of mutations only affecting this isoform in profoundly deaf patients.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

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