@article {10768, title = {Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.}, journal = {Redox Biol}, volume = {19}, year = {2018}, month = {2018 10}, pages = {301-317}, abstract = {

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2 mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2 mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2 mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 {\texttimes} 10) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.

}, keywords = {Animals, Apoptosis, Connexin 26, Female, Gene Deletion, Male, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2, Oxidation-Reduction, Presbycusis, Signal Transduction}, issn = {2213-2317}, doi = {10.1016/j.redox.2018.08.002}, author = {Fetoni, Anna Rita and Zorzi, Veronica and Paciello, Fabiola and Ziraldo, Gaia and Peres, Chiara and Raspa, Marcello and Scavizzi, Ferdinando and Salvatore, Anna Maria and Crispino, Giulia and Tognola, Gabriella and Gentile, Giulia and Spampinato, Antonio Gianmaria and Cuccaro, Denis and Guarnaccia, Maria and Morello, Giovanna and Van Camp, Guy and Fransen, Erik and Brumat, Marco and Girotto, Giorgia and Paludetti, Gaetano and Gasparini, Paolo and Cavallaro, Sebastiano and Mammano, Fabio} } @article {7740, title = {The p.Cys169Tyr variant of connexin 26 is not a polymorphism.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 May 1}, pages = {2641-8}, abstract = {

Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26 (Cx26), are the primary cause of hereditary prelingual hearing impairment. Here, the p.Cys169Tyr missense mutation of Cx26 (Cx26C169Y), previously classified as a polymorphism, has been identified as causative of severe hearing loss in two Qatari families. We have analyzed the effect of this mutation using a combination of confocal immunofluorescence microscopy and molecular dynamics simulations. At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT). The lack of the disulfide bridge in the Cx26C169Y protein causes a spatial rearrangement of two important residues, Asn176 and Thr177. In the Cx26WT protein, these residues play a crucial role in the intra-molecular interactions that permit the formation of an intercellular channel by the head-to-head docking of two opposing hemichannels resident in the plasma membrane of adjacent cells. Our results elucidate the molecular pathogenesis of hereditary hearing loss due to the connexin mutation and facilitate the understanding of its role in both healthy and affected individuals.

}, keywords = {Alleles, Amino Acid Substitution, Cell Line, Connexins, Female, Gap Junctions, Gene Expression, Genotype, Hearing Loss, Humans, Immunohistochemistry, Male, Models, Molecular, Mutation, Missense, Pedigree, Polymorphism, Genetic, Protein Conformation, Protein Interaction Domains and Motifs, Transfection}, issn = {1460-2083}, doi = {10.1093/hmg/ddv026}, author = {Zonta, Francesco and Girotto, Giorgia and Buratto, Damiano and Crispino, Giulia and Morgan, Anna and Abdulhadi, Khalid and Alkowari, Moza and Badii, Ramin and Gasparini, Paolo and Mammano, Fabio} }