%0 Journal Article
%T Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome
%A Abdelaziz Tlili
%A Alain Aghaie
%A Alice Emptoz
%A Aziz El-Amraoui
%A Christine Petit
%A Didier Dulon
%A Elise Pepermans
%A Lawrence Lustig
%A Margot Tertrais
%A Matteo Cortese
%A Olinda Alegria-Prevot
%A Omar Akil
%A Paul Avan
%A Philippe F.Y. Vincent
%A Pranav Patni
%A Saaid Safieddine
%A Samantha Papal
%A Sedigheh Delmaghani
%A Vincent Michel
%A Yohan Bouleau
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI94351
%X Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1ex4每/每) and postnatal hair cell每specific conditional (Clrn1ex4fl/fl Myo15-Cre+/每) knockout mice. Clrn1ex4每/每 mice were profoundly deaf, whereas Clrn1ex4fl/fl Myo15-Cre+/每 mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and CaV1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic CaV1.3 Ca2+ channel complex via the Cav汕2 auxiliary subunit and the PDZ domain每containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus每mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1ex4fl/fl Myo15-Cre+/每 mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients
%U https://www.jci.org/articles/view/94351