title: Assembly of the cochlear gap junction macromolecular complex requires connexin 26.
abstract: Hereditary deafness affects approximately 1 in 2,000 children. Mutations in the gene encoding the cochlear gap junction protein connexin 26 (CX26) cause prelingual, nonsyndromic deafness and are responsible for as many as 50% of hereditary deafness cases in certain populations. Connexin-associated deafness is thought to be the result of defective development of auditory sensory epithelium due to connexion dysfunction. Surprisingly, CX26 deficiency is not compensated for by the closely related connexin CX30, which is abundantly expressed in the same cochlear cells. Here, using two mouse models of CX26-associated deafness, we demonstrate that disruption of the CX26-dependent gap junction plaque (GJP) is the earliest observable change during embryonic development of mice with connexin-associated deafness. Loss of CX26 resulted in a drastic reduction in the GJP area and protein level and was associated with excessive endocytosis with increased expression of caveolin 1 and caveolin 2. Furthermore, expression of deafness-associated CX26 and CX30 in cell culture resulted in visible disruption of GJPs and loss of function. Our results demonstrate that deafness-associated mutations in CX26 induce the macromolecular degradation of large gap junction complexes accompanied by an increase in caveolar structures.
authors.forename: Kazusaku
authors.initials: K
authors.lastname: Kamiya
authors.forename: Sabrina W
authors.initials: SW
authors.lastname: Yum
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
authors.forename: Miho
authors.initials: M
authors.lastname: Muraki
authors.forename: Kana
authors.initials: K
authors.lastname: Ogawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Karasawa
authors.forename: Asuka
authors.initials: A
authors.lastname: Miwa
authors.forename: Xueshui
authors.initials: X
authors.lastname: Guo
authors.forename: Satoru
authors.initials: S
authors.lastname: Gotoh
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sugitani
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Shioko
authors.initials: S
authors.lastname: Ito-Kawashima
authors.forename: Takashi
authors.initials: T
authors.lastname: Iizuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D051243:Caveolin 2 / Q000378:metabolism; D003051:Cochlea / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004705:Endocytosis; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure; D006319:Hearing Loss, Sensorineural / Q000196:embryology / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D059748:Proteolysis
chemical_list: C495545:Cav2 protein, mouse; D051242:Caveolin 1; D051243:Caveolin 2; D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D046912:Multiprotein Complexes; D000072259:Connexin 26