ArticleGenome medicine2025
A rare haplotype of the GJD3 gene segregating in familial Meniere's disease interferes with connexin assembly.
Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 2 of them syntheses that pooled it.
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Who cites it
8 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Genome-wide analysis implicates inner ear development in Ménière disease.American journal of human genetics · 2026Pooled it
- A Systematic Review on the Role of the Stria Vascularis in Menière's Disease Pathogenesis.Journal of the Association for Research in Otolaryngology : JARO · 2025Pooled it
- Epidemiological and clinical differences in Meniere disease across European and East Asian populations.The Journal of international medical research · 2026Review
- Genome-wide analysis implicates inner ear development in Ménière's disease.medRxiv : the preprint server for health sciences · 2026Article
- Burden of novel and ultra-rare missense variants in the NF-κB pathway genes associated to Ménière's disease.Frontiers in immunology · 2026Article
- Connexins in Acquired Hearing Loss: Expanding Research Perspectives.Biomedicines · 2025Review
- Preclinical Models to Study the Molecular Pathophysiology of Meniere's Disease: A Pathway to Gene Therapy.Journal of clinical medicine · 2025Article
- Characterization of Vestibular Phenotypes in Patients with Genetic Hearing Loss.Journal of clinical medicine · 2024Article
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14 authors.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundFamilial Meniere's disease (FMD) is a rare polygenic disorder of the inner ear. Mutations in the connexin gene family, which encodes gap junction proteins, can also cause hearing loss, but their role in FMD is largely unknown.
methodsWe retrieved exome sequencing data from 94 individuals in 70 Meniere's disease (MD) families. Through gene burden analysis, we calculated the enrichment of rare variants (allele frequency < 0.05) in connexins genes in FMD individuals compared with the reference population. The connexin monomer and the homomeric connexon structural models were predicted using AlphaFold2 and HDOCK. RT-qPCR and immunofluorescence were done in mice cochleae to identify expression of the mouse ortholog candidate gene Gjd3.
resultsWe found an enrichment of rare missense variants in the GJD3 gene when comparing allelic frequencies in FMD (N = 94) with the Spanish reference population (OR = 3.9[1.92-7.91], FDR = 2.36E-03). In the GJD3 sequence, we identified a rare haplotype (TGAGT) composed of two missense, two synonymous, and one downstream variant. This haplotype was found in five individuals with FMD, segregating in three unrelated families with a total of ten individuals; and in another eight MD individuals. GJD3 encodes the gap junction protein delta 3, also known as human connexin 31.9 (Cx31.9). The protein model predicted that the NP_689343.3:p.(His175Tyr) missense variant could modify the interaction between connexins and the connexon assembly, affecting the homotypic GJD3 gap junction between cells. Our studies in mice revealed that Gjd3-encoding Gjd3 or mouse connexin 30.2 (Cx30.2)-was expressed in the organ of Corti and vestibular organs, particularly in the tectorial membrane, the base of inner and outer hair cells and the nerve fibers.
conclusionsThe present results describe a novel association between GJD3 and FMD, providing evidence that FMD is related to changes in the inner ear channels, and supporting a new role of tectorial membrane proteins in MD.
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