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© Research
Publication : The Journal of clinical investigation

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in The Journal of clinical investigation - 09 Jul 2018

Dulon D, Papal S, Patni P, Cortese M, Vincent PF, Tertrais M, Emptoz A, Tlili A, Bouleau Y, Michel V, Delmaghani S, Aghaie A, Pepermans E, Allegria-Prevot O, Akil O, Lustig L, Avan P, Safieddine S, Petit C, El-Amraoui A

Link to Pubmed [PMID] – 29985171

J. Clin. Invest. 2018 Jul;

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.

https://www.ncbi.nlm.nih.gov/pubmed/29985171