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

Journal of Clinical Investigation, ISSN: 1558-8238, Vol: 128, Issue: 8, Page: 3382-3401
2018
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Article Description

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.

Bibliographic Details

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

American Society for Clinical Investigation

Medicine

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