Research conducted by scientists at the reConnect Institute, a foundation under the auspices ofInstitut Pasteur, reveals that the compensatory interaction between the proteins associated with hearing loss, clarin-1 and clarin-2, governs the variability of hearing impairments in individuals with Usher syndrome type 3. The study, published on April 9 , 2026 , in Advanced Science, was conducted at theHearing Institute ( Institut Pasteur Center, Inserm, CNRS) by Maureen Wentling, a doctoral student, under the joint supervision of Sedigheh Delmaghani and Aziz El Amraoui, within the “Progressive Sensory Deficits, Pathophysiology, and Therapy” team. The researchers demonstrated for the first time the essential and complementary roles of the clarin-1 and clarin-2 proteins in auditory function, opening up new therapeutic prospects for hereditary hearing loss, including Usher syndrome type 3 (USH3).
A rare disease with variable symptoms
Usher syndrome is a rare disorder that is the leading cause of hereditary deafblindness, affecting 1 in 20,000 people in Europe. There are three forms (types 1, 2, and 3), which differ in the severity of hearing loss, the extent of balance impairment, and the age at which visual symptoms appear. Type 3 is characterized by progressive hearing loss and significant variability among individuals with the syndrome, even when the genetic mutation is identical. Until now, this variability has remained poorly understood.
A key interaction between two proteins
In this study, researchers at the reConnect Institute demonstrate that this syndrome is actually driven by a network of genes. Specifically, the level of activity of the clarin-2 protein modulates the severity of mutations in the CLRN1 gene, which explains the marked phenotypic variability observed in individuals with USH3 who carry identical mutations.
This research reveals that the proteins clarin-1 and clarin-2 act in concert. These two proteins play a vital role in the hair cells of the inner ear, which convert sound into electrical signals. When these two proteins are absent, the entire sound transduction mechanism breaks down. In particular, the structures at the tips of the auditory sensory cells become disorganized, and the neurons involved in hearing undergo progressive degeneration.
"This study represents a major breakthrough in our understanding of the molecular mechanisms underlying progressive hearing loss, as it identifies, for the first time, the compensatory and essential role of the Clarin-1 and Clarin-2 proteins in hearing. It redefines CLRN1-associated hearing loss as a disease dependent on a molecular network, thereby opening up new therapeutic avenues for people affected by USH3 syndrome," says Sedigheh Delmaghani, a researcher at the reConnect Institute ( Institut Pasteur Center).
Toward Better Screening
This research opens up new possibilities for improving the management of hearing loss in people affected by this syndrome. The goal remains to intervene as early as possible and preserve hearing to the greatest extent possible. By demonstrating that Usher syndrome type III is caused by a complex network of genes, this discovery paves the way for new diagnostic and therapeutic approaches.
"This study therefore recommends systematically including the CLRN2 gene in genetic testing for USH3 patients, as pathogenic mutations in this gene significantly worsen hearing loss. Furthermore, cochlear implantation performed before neuronal degeneration could be a potential approach to preserving hearing in individuals with mutations in CLRN1 and CLRN2 by directly stimulating auditory neurons," explains Sedigheh Delmaghani.
Reference:
M. Wentling, A. Yakhlef Sanchez, N. Thelen, et al. “Compensatory Interplay Between Clarin-1 and Clarin-2 Deafness-Associated Proteins Governs Phenotypic Variability in Hearing.” *Advanced Science* (2026): e21853. https://doi.org/10.1002/advs.202521853
