RT Journal Article
T1 A rare haplotype of the GJD3 gene segregating in familial Meniere’s disease interferes with connexin assembly
A1 Escalera Balsera, Alba
A1 Robles Bolivar, Paula
A1 Parra Pérez, Alberto M
A1 Murillo Cuesta, Silvia
A1 Chow Chua, Han
A1 Rodríguez de la Rosa, Lourdes
A1 Contreras Rodríguez, Julio
A1 Domarecka, Ewa
A1 Amor-Dorado, Juan Carlos
A1 Soto Varela, Andrés
A1 Varela-Nieto, Isabel
A1 Szczepek, Agnieszka J
A1 Gallego Martínez, Álvaro
A1 López Escámez, José A
AB 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.
PB BioMed Central
SN 1756-994X
YR 2025
FD 2025-01-15
LK https://hdl.handle.net/20.500.14352/116942
UL https://hdl.handle.net/20.500.14352/116942
LA eng
NO Escalera-Balsera, A., Robles-Bolivar, P., Parra-Perez, A. M., Murillo-Cuesta, S., Chua, H. C., Rodríguez-de la Rosa, L., Contreras, J., Domarecka, E., Amor-Dorado, J. C., Soto-Varela, A., Varela-Nieto, I., Szczepek, A. J., Gallego-Martinez, A., & Lopez-Escamez, J. A. (2025). A rare haplotype of the GJD3 gene segregating in familial Meniere's disease interferes with connexin assembly. Genome medicine, 17(1), 4. https://doi.org/10.1186/s13073-024-01425-1
NO Contributions:Conceptualization: A.E.-B. and J.A.L.-E.; methodology: A.E.-B., P.R.-B., A.M.P.-P., C.H.C., L.R.-dlR., J.C., and E.D.; software: A.E.-B., A.M.P.-P., and A.G.-M.; formal analysis: A.E.-B.; investigation: A.E.-B., S.M.-C., C.H.C., and A.G.-M.; interpretation of data: A.E.-B., P.R.-B., A.M.P.-P., S.M.-C., C.H.C., L.R.-dlR., J.C., E.D., J.C.A.-D., A.S.-V., I.V.-N., A.J.S., A.G.-M., and J.A.L.-E.; resources: J.C.A.-D., A.S.-V., I.V.-N., A.J.S., and J.A.L.-E.; data curation: A.E.-B.; writing—original draft preparation: A.E.-B. and J.A.L.-E.; writing—review and editing: A.E.-B., P.R.-B., A.M.P.-P., S.M.-C., C.H.C., L.R.-dlR., J.C., E.D., J.C.A.-D., A.S.-V., I.V.-N., A.J.S., A.G.-M., and J.A.L.-E.; visualization: A.E.-B., P.R.-B., and A.M.P.-P.; supervision: I.V.-N., A.J.S., A.G.-M., and J.A.L.-E.; project administration: J.A.L.-E.; funding acquisition: J.A.L.-E. All authors read and approved the final manuscript.
NO The University of Sydney
NO Junta de Andalucia
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Ministerio de Economía, Comercio y Empresa (España)
DS Docta Complutense
RD 18 dic 2025