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

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Dulon, Didier | Papal, Samantha | Patni, Pranav | Cortese, Matteo | Vincent, Philippe F.y | Tertrais, Margot | Emptoz, Alice | Tlili, Abdelaziz | Bouleau, Yohan | Michel, Vincent | Delmaghani, Sedigheh | Aghaie, Alain | Pepermans, Elise | Alegria-Prevot, Olinda | Akil, Omar | Lustig, Lawrence | Avan, Paul | Safieddine, Saaid | Petit, Christine | El-Amraoui, Aziz

Edité par CCSD ; American Society for Clinical Investigation -

International audience. 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.

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