Cx26 heterozygous mutations cause hyperacusis-like hearing sensitivity enhancement and increase susceptibility to noise

Gap junction gene GJB2 (Cx26) mutations cause >50% of nonsyndromic hearing loss. Its recessive hetero-mutation carriers, who have no deafness, occupy ∼10-20% of the general population. Here, we report an unexpected finding that these heterozygote carriers have hearing over-sensitivity and active cochlear amplification increased. Mouse models show that Cx26 hetero-deletion reduced endocochlear potential (EP) generation in the cochlear lateral wall and caused outer hair cell electromotor protein prestin compensatively upregulated to increase active cochlear amplification and hearing sensitivity. The increase of active cochlear amplification also increased sensitivity to noise; exposure of daily-level noise could cause Cx26+/- mice permanent hearing threshold shift leading to hearing loss. This study demonstrate that Cx26 recessive heterozygous mutations are not ‘harmless’ for hearing as previously considered and can cause hyperacusis-like hearing over-sensitivity. The data also indicate that GJB2 hetero-mutation carriers are vulnerable to noise and should avoid noise exposure in daily-life. Teaser Cx26 hetero-mutations are not harmless and can cause hearing over-sensitivity and increase susceptibility to noise.