A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly
Abstract Background Familial 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. Methods We retrieved exome sequencing data from 94 in...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s13073-024-01425-1 |
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| author | Alba Escalera-Balsera Paula Robles-Bolivar Alberto M. Parra-Perez Silvia Murillo-Cuesta Han Chow Chua Lourdes Rodríguez-de la Rosa Julio Contreras Ewa Domarecka Juan Carlos Amor-Dorado Andrés Soto-Varela Isabel Varela-Nieto Agnieszka J. Szczepek Alvaro Gallego-Martinez Jose A. Lopez-Escamez |
| author_facet | Alba Escalera-Balsera Paula Robles-Bolivar Alberto M. Parra-Perez Silvia Murillo-Cuesta Han Chow Chua Lourdes Rodríguez-de la Rosa Julio Contreras Ewa Domarecka Juan Carlos Amor-Dorado Andrés Soto-Varela Isabel Varela-Nieto Agnieszka J. Szczepek Alvaro Gallego-Martinez Jose A. Lopez-Escamez |
| author_sort | Alba Escalera-Balsera |
| collection | DOAJ |
| description | Abstract Background Familial 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. Methods We 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. Results We 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. Conclusions The 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. |
| format | Article |
| id | doaj-art-18c22a7040af4895b3360f5644fe13f6 |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Genome Medicine |
| spelling | doaj-art-18c22a7040af4895b3360f5644fe13f62025-01-19T12:33:56ZengBMCGenome Medicine1756-994X2025-01-0117111610.1186/s13073-024-01425-1A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assemblyAlba Escalera-Balsera0Paula Robles-Bolivar1Alberto M. Parra-Perez2Silvia Murillo-Cuesta3Han Chow Chua4Lourdes Rodríguez-de la Rosa5Julio Contreras6Ewa Domarecka7Juan Carlos Amor-Dorado8Andrés Soto-Varela9Isabel Varela-Nieto10Agnieszka J. Szczepek11Alvaro Gallego-Martinez12Jose A. Lopez-Escamez13Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitario, Ibs.GRANADA, Universidad de GranadaOtology & Neurotology Group CTS495, Instituto de Investigación Biosanitario, Ibs.GRANADA, Universidad de GranadaOtology & Neurotology Group CTS495, Instituto de Investigación Biosanitario, Ibs.GRANADA, Universidad de GranadaSensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERERSydney Pharmacy School, Faculty of Medicine and Health and Charles Perkins Centre, The University of SydneySensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERERSensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERERDepartment of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu BerlinDepartment of Otolaryngology, Hospital Can MissesHealth Research Institute of Santiago de Compostela (IDIS)Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERERDepartment of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu BerlinOtology & Neurotology Group CTS495, Instituto de Investigación Biosanitario, Ibs.GRANADA, Universidad de GranadaOtology & Neurotology Group CTS495, Instituto de Investigación Biosanitario, Ibs.GRANADA, Universidad de GranadaAbstract Background Familial 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. Methods We 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. Results We 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. Conclusions The 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.https://doi.org/10.1186/s13073-024-01425-1Meniere’s diseaseHearing lossInner earTectorial membraneExome sequencingBioinformatics |
| spellingShingle | Alba Escalera-Balsera Paula Robles-Bolivar Alberto M. Parra-Perez Silvia Murillo-Cuesta Han Chow Chua Lourdes Rodríguez-de la Rosa Julio Contreras Ewa Domarecka Juan Carlos Amor-Dorado Andrés Soto-Varela Isabel Varela-Nieto Agnieszka J. Szczepek Alvaro Gallego-Martinez Jose A. Lopez-Escamez A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly Genome Medicine Meniere’s disease Hearing loss Inner ear Tectorial membrane Exome sequencing Bioinformatics |
| title | A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly |
| title_full | A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly |
| title_fullStr | A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly |
| title_full_unstemmed | A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly |
| title_short | A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly |
| title_sort | rare haplotype of the gjd3 gene segregating in familial meniere s disease interferes with connexin assembly |
| topic | Meniere’s disease Hearing loss Inner ear Tectorial membrane Exome sequencing Bioinformatics |
| url | https://doi.org/10.1186/s13073-024-01425-1 |
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