title: Deafness induced by Connexin 26 (GJB2) deficiency is not determined by endocochlear potential (EP) reduction but is associated with cochlear developmental disorders.
abstract: Connexin 26 (Cx26, GJB2) mutations are the major cause of hereditary deafness and are responsible for >50% of nonsyndromic hearing loss. Mouse models show that Cx26 deficiency can cause congenital deafness with cochlear developmental disorders, hair cell degeneration, and the reduction of endocochlear potential (EP) and active cochlear amplification. However, the underlying deafness mechanism still remains undetermined. Our previous studies revealed that hair cell degeneration is not a primary cause of hearing loss. In this study we investigated the role of EP reduction in Cx26 deficiency-induced deafness. We found that the EP reduction is not associated with congenital deafness in Cx26 knockout (KO) mice. The threshold of auditory brainstem response (ABR) in Cx26 KO mice was even greater than 110 dB SPL, demonstrating complete hearing loss. However, the EP in Cx26 KO mice varied and not completely abolished. In some cases, the EP could still remain at higher levels (>70 mV). We further found that the deafness in Cx26 KO mice is associated with cochlear developmental disorders. Deletion of Cx26 in the cochlea before postnatal day 5 (P5) could cause congenital deafness. The cochlea had developmental disorders and the cochlear tunnel was not open. However, no congenital deafness was found when Cx26 was deleted after P5. The cochlea also displayed normal development and the cochlear tunnel was open normally. These data suggest that congenital deafness induced by Cx26 deficiency is not determined by EP reduction and may result from cochlear developmental disorders.
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.; Department of Otolaryngology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Liang
authors.affiliation: Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.. Electronic address: hzhao2@uky.edu.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003051:Cochlea / Q000254:growth & development* / Q000502:physiology; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D003638:Deafness / Q000151:congenital*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D017630:Connexins; C000607043:Gjb2 protein, mouse; D000072259:Connexin 26
keywords: Connexin; Cx26; Deafness; EP; Gap junction; Inner ear development
references.citation: Front Biosci (Landmark Ed). 2011 Jun 01;16:3252-74
references.pmid: 21622233
references.citation: Cell Tissue Res. 2008 Sep;333(3):395-403
references.pmid: 18581144
references.citation: J Physiol. 2006 Oct 1;576(Pt 1):11-21
references.pmid: 16857713
references.citation: Neuroscience. 2009 Dec 15;164(3):1312-9
references.pmid: 19712724
references.citation: Biochem Biophys Res Commun. 2014 Feb 28;445(1):71-7
references.pmid: 24491564
references.citation: J Comp Neurol. 2006 Nov 20;499(3):506-18
references.pmid: 16998915
references.citation: Clin Genet. 2006 May;69(5):371-92
references.pmid: 16650073
references.citation: J Comp Neurol. 2009 Oct 20;516(6):569-79
references.pmid: 19673007
references.citation: J Membr Biol. 2006 Feb-Mar;209(2-3):177-86
references.pmid: 16773501
references.citation: Dev Dyn. 2006 Nov;235(11):2991-8
references.pmid: 16958097
references.citation: Pediatrics. 1998 Feb;101(2):221-8
references.pmid: 9445495
references.citation: Curr Opin Neurobiol. 2008 Aug;18(4):370-6
references.pmid: 18809494
references.citation: Antioxid Redox Signal. 2009 Feb;11(2):283-95
references.pmid: 18831677
references.citation: Hum Mol Genet. 2003 Jan 1;12(1):13-21
references.pmid: 12490528
references.citation: Neuron. 2008 Aug 28;59(4):530-45
references.pmid: 18760690
references.citation: Neuroscience. 2008 Oct 28;156(4):1039-47
references.pmid: 18793701
references.citation: Biochem Biophys Res Commun. 2009 Jul 17;385(1):33-7
references.pmid: 19433060
references.citation: Nature. 1997 May 1;387(6628):80-3
references.pmid: 9139825
references.citation: Neuroscience. 2014 Apr 18;265:137-46
references.pmid: 24480364
references.citation: Neurosci Lett. 2012 Oct 18;528(1):36-41
references.pmid: 22975134
references.citation: Curr Biol. 2002 Jul 9;12(13):1106-11
references.pmid: 12121617
references.citation: Nat Commun. 2013;4:1786
references.pmid: 23653198