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J Clin Invest. 2018 Aug 1;128(8):3382-3401. doi: 10.1172/JCI94351. Epub 2018 Jul 9.

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

Dulon D1,2, Papal S1,3,4, Patni P1,3,4, Cortese M1,3,4, Vincent PF1,2, Tertrais M1,2, Emptoz A1,3,4, Tlili A1,3,4, Bouleau Y1,2, Michel V1,3,4, Delmaghani S1,3,4, Aghaie A1,3,4, Pepermans E1,3,4, Alegria-Prevot O1,3,4, Akil O5, Lustig L6, Avan P7, Safieddine S1,3,4,8, Petit C1,3,4,9, El-Amraoui A1,3,4.

Author information

UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
Université de Bordeaux, Laboratoire de Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, Bordeaux, France.
Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France.
Sorbonne Universités, Complexité du Vivant, Paris, France.
Department of Otolaryngology-Head and Neck Surgery, UCSF, San Francisco, California, USA.
Department of Otolaryngology-Head and Neck Surgery, Columbia University Medical Center, New York, New York, USA.
Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Université d'Auvergne; Biophysique Médicale, Centre Jean Perrin, Clermont-Ferrand, France.
Centre National de la Recherche Scientifique, Paris, France.
Collège de France, Paris, France.


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.


Calcium channels; Gene therapy; Neuroscience; Synapses

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