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Compensatory Interplay Between Clarin-1 and Clarin-2 Deafness-Associated Proteins Governs Phenotypic Variability in
Maureen Wentling1,2, Aïda Yakhlef Sanchez1,3, Nicolas Thelen4
1Institut Pasteur, Institut De L'audition, AP-HP, INSERM U1335, CNRS, Fondation Pour l'Audition, IHU reConnect, Progressive Sensory Disorders, Pathophysiology and Therapy, Université Paris Cité, Paris, France.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 23, 2026
Summary
Clarin-1 and clarin-2 proteins compensate for each other, influencing hearing and balance. Their combined loss worsens Usher syndrome type III (USH3) hearing loss, suggesting CLRN2
Area of Science:
- Genetics
- Neuroscience
- Otolaryngology
Background:
- Usher syndrome type III (USH3) involves progressive hearing loss, vestibular issues, and retinitis pigmentosa, caused by CLRN1 mutations.
- CLRN2 mutations are linked to progressive, non-syndromic hearing loss.
- Phenotypic variability in USH3 suggests genetic interactions, potentially involving CLRN2.
Purpose of the Study:
- Investigate the functional interplay between CLRN1 and CLRN2.
- Determine the combined effect of Clrn1 and Clrn2 loss on hearing and inner ear function.
- Explore CLRN2's role in USH3 variability.
Main Methods:
- Generated Clrn1-/-Clrn2-/- double knockout mice.
- Performed RNA-sequencing and functional/physiological analyses.
- Compared phenotypes of double knockout mice with single knockout mice.
Main Results:
- Clarin-1 and clarin-2 jointly regulate key inner ear functions: mechanoelectrical transduction, ionic homeostasis, and synaptic organization.
- Combined loss of Clrn1 and Clrn2 results in a more severe hearing phenotype than individual gene loss, indicating functional compensation.
- CLRN2 variants may worsen hearing loss in USH3 patients.
Conclusions:
- Clarin-1 and clarin-2 exhibit a compensatory interplay in the inner ear.
- USH3 can be viewed as a network-dependent disorder due to gene interactions.
- Findings support including CLRN2 in genetic screening for USH3 and provide a basis for therapeutic strategies.
Keywords:
Clarin‐1 and Clarin‐2Usher syndrome type IIIhearing phenotypic variabilityion homeostasismechanoelectrical transductionsynaptopathyMore Related Videos
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