Clarin‐1 and Clarin‐2; Usher syndrome type III; hearing phenotypic variability; ion homeostasis; mechanoelectrical transduction; synaptopathy
Abstract :
[en] Usher syndrome type III (USH3) is a genetic disorder characterized by progressive, post-lingual hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa. USH3 is caused by mutations in CLRN1, which encodes clarin-1, a tetraspanin-like protein. Mutations in CLRN2, which encodes the related protein clarin-2, are also implicated in progressive, non-syndromic hearing loss in both humans and mice. USH3 patients show considerable phenotypic variability, even among individuals with the same mutation. This variability may result from environmental factors or interactions with other inner ear genes, such as CLRN2. To investigate the functional interplay of these genes, we generated Clrn1- /-Clrn2-/- double knockout mice. RNA-sequencing and functional/physiological analyses revealed that clarin-1 and clarin-2 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to Clrn1-/- and Clrn2-/- mice, which reveals a functional compensation between them. CLRN2 variants may exacerbate hearing loss in USH3 patients, supporting inclusion of CLRN2 in genetic screening. By revealing a functional, compensatory interplay between clarin-1 and clarin-2, this study reframes CLRN1-associated deafness as a network-dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.
Wentling, Maureen; Institut 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 ; Collège Doctoral ED515, Sorbonne Université, Paris, France
Yakhlef Sanchez, Aïda; Institut 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 ; Collège Doctoral ED158, Sorbonne Université, Paris, France
Thelen, Nicolas ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Senarisoy, Müge; Institut 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
Hogg, Maria; Institut 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
Condamine, Steven; Laboratoire De Neurophysiologie de La Synapse Auditive, Institut De L'audition and Université de Bordeaux, Bordeaux, France
Lelli, Andrea; Institut Pasteur, Institut De L'audition, AP-HP, INSERM, CNRS, Fondation Pour l'Audition, IHU reConnect, Auditory Therapies Innovation Laboratory, Université Paris Cité, Paris, France
Wysocka, Emilia; Institut 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
Patni, Pranav; Institut 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 ; Collège Doctoral ED515, Sorbonne Université, Paris, France
Vitry, Sandrine; Institut 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
Yildizhan, Kerem Yasin; Institut 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
Le Gal, Sébastien; Institut 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
Nouaille, Sylvie; Institut 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
Bowl, Michael R; UCL Ear Institute, University College London, London, UK
Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > Service collectif des enseignements de biologie en bachelier ; Collège Doctoral ED158, Sorbonne Université, Paris, France
Dulon, Didier; Laboratoire De Neurophysiologie de La Synapse Auditive, Institut De L'audition and Université de Bordeaux, Bordeaux, France
Delmaghani, Sedigheh ; Institut 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
El-Amraoui, Aziz; Institut 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
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