title: Connexin26 (GJB2) deficiency reduces active cochlear amplification leading to late-onset hearing loss.
abstract: Connexin26 (Cx26, GJB2) mutations account for >50% of nonsyndromic hearing loss. The deafness is not always congenital. A large group of these patients (∼30%) demonstrate a late-onset hearing loss, starting in childhood. They have normal hearing early in life and are therefore good candidates for applying protective and therapeutic interventions. However, the underlying deafness mechanism is unclear. In this study, we used a time-controlled, inducible gene knockout technique to knockout Cx26 expression in the cochlea after birth. We found that deletion of Cx26 after postnatal day 5 (P5) in mice could lead to late-onset hearing loss. Similar to clinical observations, the mice demonstrated progressive, mild to moderate hearing loss. The hearing loss initiated at high frequencies and then extended to the middle- and low-frequency range. The cochlea showed normal development and had no apparent hair cell loss. However, distortion product otoacoustic emission (DPOAE) was reduced. The reduction was also progressive and large at high-frequencies. Consistent with DPOAE reduction, we found that outer hair cell electromotility-associated nonlinear capacitance was shifted to the right and the slope of voltage dependence was reduced. The endocochlear potential was reduced in Cx26 conditional knockout (cKO) mice but the reduction was not associated with progressive hearing loss. These data suggest that Cx26 deficiency may impair active cochlear amplification leading to late-onset hearing loss. Our study also helps develop newer protective and therapeutic interventions to this common nonsyndromic hearing loss.
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: C
authors.initials: C
authors.lastname: Liang
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: L
authors.initials: L
authors.lastname: Zong
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
authors.forename: R O
authors.initials: RO
authors.lastname: Jones
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States. Electronic address: hzhao2@uky.edu.
authors.forename: H-B
authors.initials: HB
authors.lastname: Zhao
mesh_terms: D017668:Age of Onset; D000818:Animals; D002452:Cell Count; D003051:Cochlea / Q000473:pathology / Q000503:physiopathology*; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D025802:Electric Capacitance; D005455:Fluorescent Antibody Technique; D018072:Hair Cells, Auditory, Outer / Q000473:pathology / Q000502:physiology*; D034381:Hearing Loss / Q000473:pathology / Q000503:physiopathology*; D018345:Mice, Knockout; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D018408:Patch-Clamp Techniques; D012720:Severity of Illness Index
chemical_list: D000075302:Connexin 30; D017630:Connexins; C000607043:Gjb2 protein, mouse; C100629:Gjb6 protein, mouse; D000072259:Connexin 26
keywords: Cx26; active cochlear amplification; connexin; deafness; gap junction; inner ear