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Compensatory interplay between clarin-1 and 1 clarin-2 deafness-associated proteins govern phenotypic variability in hearing

ABSTRACT: Usher syndrome type III (USH3), caused by mutations in CLRN1 encoding clarin-1, presents with progressive hearing loss, vestibular dysfunction, and retinitis pigmentosa, with striking phenotypic variability even among patients sharing identical mutations. Clarin-1's paralog, clarin-2 (encoded by CLRN2), is similarly implicated in hearing loss, suggesting potential functional interplay between these proteins. To investigate this relationship, we conducted RNA-sequencing of cochlear tissues from Clrn1-/-, Clrn2-/-, and Clrn1-/-Clrn2-/- double-knockout mice, revealing that clarin-1 and clarin-2 cooperatively regulate essential auditory processes, including mechanoelectrical transduction, ionic homeostasis, and synaptic organization. The double knockout mice exhibited synergistic disruption of these pathways, resulting in more severe hearing deficits than either single knockout, demonstrating that these proteins functionally compensate for one another. These findings suggest that CLRN2 variants may influence hearing outcomes in USH3 patients, supporting the integration of CLRN2 analysis into genetic diagnostics. By demonstrating that clarin-1 and clarin-2 share overlapping functional roles in the inner ear, this study redefines USH3 as a network-dependent disorder, offering new insights for therapeutic development. The RNA-seq dataset provides a comprehensive resource for exploring gene interactions in auditory function and advancing precision medicine approaches for hearing loss.

ORGANISM(S): Mus musculus

PROVIDER: GSE312253 | GEO | 2026/02/24

REPOSITORIES: GEO

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Project description:We performed a microarray analysis of auditory midbrain (inferior colliculus, IC) mRNA from young adult CBA mice (controls) with good hearing, middle aged (MA) with good hearing, and old mild (MP) and severe (SP) presbycusic CBA mice. Fold Change data derived from RMA normalization revealed that the overall GABA receptor alpha 6 expression profiles for MA, MP and SP were down-regulated relative to young adult controls with good hearing. Relative real-time PCR for five GABA receptors confirmed this age-related down regulation quantitatively. Functional hearing data: Auditory Brainstem Responses (ABR) enriched the analysis to select the probe-sets that changed with age and hearing loss by the linear regression best-fit line model technique. GABA receptor genotype-phenotype correlations with auditory functional data indicated that GABA-receptor subtypes are under expressed in SP mice. Hierarchical clustering (HC) analyses yielded statistical significance of normalized GeneChip data Real-time PCR showed that Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1 may be involved in physiological changes that occur in age-related hearing loss. Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. In this study we analyzed gene expression for a set of GABA receptors in the inferior colliculus of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing changes from RMA normalized microarray data (39 replicates) in four age-groups, Young Controls and Middle aged mice with good hearing, mild and sever e presbycusis from old mice. Fold change gene expression derived from RMA normalized data were first subjected to one-way ANOVA, and then linear regression was performed. The selected gene expression changes were confirmed by relative real-time relative to young adult controls with good hearing. Statistically significant and real time PCR confirmed GABA receptor genes; Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1, may be involved in physiological changes that occur in age-related hearing loss. Lastly, gene expression measures of each age group were correlated with pathway/network relationships relevant to the inferior colliculus using Pathway Architect, to identify key pathways consistent with the gene expression changes observed In the study of Expression changes in IC GABA receptors in the Auditory Midbrain of young adult and aging presbycusis mice total of thirty nine chips were used. The normal aging mice were in Four groups Young adults Controls with good hearing (8 mice, 8 MOE430A GeneChips), Middle aged group with good hearing ( 17 mice, 17 MOE430A GeneChips), Mild Presbycusis with limited hearing loss (9 mice, 9 MOE430A GeneChips) and Severe Presbycusis (5 mice, 5 MOE430A GeneChips).

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Compensatory interplay between clarin-1 and 1 clarin-2 deafness-associated proteins govern phenotypic variability in hearing

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