ArticleThe Journal of clinical investigation2018
Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 134 citations in OpenAlex.
- AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.Nature medicine · 2025Trial
- Review
- CLRN1 Variants in Müller Cells Cause Mitochondrial Dysfunction in USH3A Retinal Organoids.CNS neuroscience & therapeutics · 2026Article
- Single-cell analysis reveals impaired Müller glia-mediated intercellular communication and photoreceptor pathology in USH1C retinal organoids.Cellular and molecular life sciences : CMLS · 2026Article
- Compensatory Interplay Between Clarin-1 and Clarin-2 Deafness-Associated Proteins Governs Phenotypic Variability in Hearing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Gene supplementation with precise transgene expression rescues hearing loss in a mouse model with an Mpzl2 East Asian founder variant.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- AAV-mediated exon skipping therapy for Usher syndrome, type 2A.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea.Nature communications · 2025Article
- Medial Olivocochlear Efferent Modulation of Cochlear Micromechanics Requires P2X4 Receptor in Outer Hair Cells.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Adeno-associated virus-based rescue of Myo7a expression restores hair-cell function and improves hearing thresholds in a USH1B mouse strain.The Journal of physiology · 2025Article
- Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.The Journal of clinical investigation · 2025Article
- Microneedle-mediated intracochlear injection safely achieves higher perilymphatic dexamethasone concentration than intratympanic delivery in guinea pig.Drug delivery and translational research · 2025Article
- IsMedComm · 2025Article
- Exploring AAV-Mediated Gene Therapy for Inner Ear Diseases: from Preclinical Success to Clinical Potential.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Cochlear gene therapy restores hearing and auditory processing in an atypical DFNB9 mouse model.Communications medicine · 2025Article
- Advancing precision ear medicine: leveraging animal models for disease insights and therapeutic innovations.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Cochlear Implantation Outcomes in Genotyped Subjects with Sensorineural Hearing Loss.Journal of the Association for Research in Otolaryngology : JARO · 2025Article
- Inner Ear Gene Therapy: An Overview from Bench to Bedside.Molecular diagnosis & therapy · 2025Review
- The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors.PLoS genetics · 2025Article
- The predawn dilemma in adeno-associated virus-based gene therapies for hereditary deafness.American journal of stem cells · 2025Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.