TY - JOUR
T1 - Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome
AU - Dulon, Didier
AU - Papal, Samantha
AU - Patni, Pranav
AU - Cortese, Matteo
AU - Vincent, Philippe F.Y.
AU - Tertrais, Margot
AU - Emptoz, Alice
AU - Tlili, Abdelaziz
AU - Bouleau, Yohan
AU - Michel, Vincent
AU - Delmaghani, Sedigheh
AU - Aghaie, Alain
AU - Pepermans, Elise
AU - Alegria-Prevot, Olinda
AU - Akil, Omar
AU - Lustig, Lawrence
AU - Avan, Paul
AU - Safieddine, Saaid
AU - Petit, Christine
AU - El-Amraoui, Aziz
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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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U2 - 10.1172/JCI94351
DO - 10.1172/JCI94351
M3 - Article
C2 - 29985171
AN - SCOPUS:85051253894
SN - 0021-9738
VL - 128
SP - 3382
EP - 3401
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -