Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

A.R. Fetoni, V. Zorzi, F. Paciello, G. Ziraldo, C. Peres, M. Raspa, F. Scavizzi, A.M. Salvatore, G. Crispino, G. Tognola, G. Gentile, A.G. Spampinato, D. Cuccaro, M. Guarnaccia, G. Morello, G. Van Camp, E. Fransen, M. Brumat, G. Girotto, G. PaludettiP. Gasparini, S. Cavallaro, F. Mammano

Research output: Contribution to journalArticlepeer-review


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 × 10−2) 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. © 2018 The Authors
Original languageEnglish
Pages (from-to)301-317
Number of pages17
JournalRedox Biology
Publication statusPublished - 2018


  • connexin 26
  • glutathione
  • transcription factor Nrf2
  • transforming growth factor beta1
  • Nfe2l2 protein, mouse
  • transcription factor Nrf2, adult
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • apoptosis
  • Article
  • Asia
  • cochlea duct
  • cohort analysis
  • controlled study
  • Europe
  • evoked brain stem auditory response
  • female
  • gap junction
  • gene expression regulation
  • genetic association
  • genome-wide association study
  • heterozygote
  • human
  • inner ear disease
  • major clinical study
  • male
  • metabolic regulation
  • molecular pathology
  • mouse
  • neuroepithelium
  • nonhuman
  • otoacoustic emission
  • oxidation reduction reaction
  • oxidative stress
  • phenotype
  • presbyacusis
  • priority journal
  • PRKCE gene
  • protein depletion
  • TGFB1 gene
  • transcription regulation
  • animal
  • C57BL mouse
  • gene deletion
  • genetics
  • metabolism
  • signal transduction, Animals
  • Apoptosis
  • Connexin 26
  • Female
  • Gene Deletion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2
  • Oxidation-Reduction
  • Presbycusis
  • Signal Transduction


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