Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome - Université Clermont Auvergne Accéder directement au contenu
Article Dans Une Revue Journal of Clinical Investigation Année : 2018

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Paul Avan

Résumé

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–/–) and postnatal hair cell–specific conditional (Clrn1ex4fl/fl Myo15-Cre+/–) knockout mice. Clrn1ex4–/– mice were profoundly deaf, whereas Clrn1ex4fl/fl Myo15-Cre+/– 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 Cavβ2 auxiliary subunit and the PDZ domain–containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus–mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1ex4fl/fl Myo15-Cre+/– mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients.
Fichier principal
Vignette du fichier
Dulon_ElAmraoui_2017.pdf (29.02 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

pasteur-01858480 , version 1 (20-08-2018)

Licence

Paternité - Pas d'utilisation commerciale - Partage selon les Conditions Initiales

Identifiants

Citer

Didier Dulon, Samantha Papal, Pranav Patni, Matteo Cortese, Philippe F.y Vincent, et al.. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome. Journal of Clinical Investigation, 2018, 128 (8), pp.3382 - 3401. ⟨10.1172/JCI94351⟩. ⟨pasteur-01858480⟩
959 Consultations
186 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More