Towards a better understanding of the origins of phenotypic variability in the Type 3 of Usher syndrome

Research conducted by scientists at the Institut reConnect, a foundation under the aegis of the Institut Pasteur, reveals that the compensatory interaction between 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 the Hearing Institute (Pasteur Institute Center, Inserm, CNRS) by Maureen Wentling, a doctoral student, under the supervision of Sedigheh Delmaghani and Aziz El Amraoui, within the “Progressive Sensory Deficits, Pathophysiology, and Therapy” team. The researchers have 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 type 3 Usher syndrome (USH3).  

A rare disease with a wide range of form  

Usher syndrome is a rare syndrome 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 was poorly understood.

A key interaction between two proteins  

In this study, researchers at the Institut reConnect showed that this syndrome is actually driven by a network of genes. Specifically, the activity level 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 clarin-1 and clarin-2 proteins function in concert. These two proteins together play an essential role in the hair cells of the inner ear, which convert sounds into electrical signals. When these two proteins are absent, the entire sound transduction machinery 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 Usher syndrome type 3" says Sedigheh Delmaghani, a researcher at the Institut reConnect (Pasteur Institute/Inserm/CNRS Center). 

Scanning electron microscope pictures showing the complete disruption of the structures at the tips of auditory sensory cells in the absence of the genes encoding clarin-1 and clarin-2, compared to a normal cell. 

Toward a 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 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, a cochlear implant performed before neuronal degeneration sets in could be a potential strategy for preserving hearing in individuals with mutations in CLRN1 and CLRN2, by directly stimulating the 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