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

Elise Pepermans (1) , Michel Vittot (1) , Richard Goodyear (2) , Crystel Bonnet (3) , Samia Abdi (4) , Typhaine Dupont (1) , Souad Gherbi (5) , Muriel Holder (6) , Mohamed Makrelouf (7) , Jean-Pierre Hardelin (1) , Sandrine Marlin (3) , Akila Zenati (7) , Guy Richardson (2) , Paul Avan (8, 9, 10) , Amel Bahloul (1) , Christine Petit (11, 1)

1 Collège de France - Chaire Génétique et physiologie cellulaire
2 School of Life Sciences
3 Syndrome de Usher et autres atteintes rétino-cochléaires
4 Génétique et Biologie
5 Centre de référence des Surdités Génétiques
6 Service de Génétique clinique
7 Laboratoire de Biochimie Génétique
8 UNICANCER/CJP - Centre Jean Perrin [Clermont-Ferrand]
9 Neuro-Dol - Neuro-Dol
10 Equipe Biophysique Neurosensorielle [Neuro-Dol]
11 Institut de la Vision

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.

Keywords: auditory mechano-electrical transduction; deafness; protocadherin-15; stereocilia; tip-link Subject Categories Genetics; Gene Therapy & Genetic Disease; Neuroscience

Domains: Life Sciences [q-bio]; Human health and pathology; Sensory Organs; Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular Networks [q-bio.MN]

Elise Pepermans, Michel Vittot, Richard Goodyear, Crystel Bonnet, Samia Abdi, et al.. The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells. EMBO Molecular Medicine, 2014, 6 (7), pp.984-92. ⟨10.15252/emmm.201403976⟩. ⟨pasteur-01237053⟩