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Assembly of the cochlear gap junction macromolecular complex requires connexin 26

Assembly of the cochlear gap junction macromolecular complex requires connexin 26

Authors :
Kazusaku Kamiya
Sabrina W. Yum
Satoru Gotoh
Osamu Minowa
Keiko Karasawa
Takashi Sakurai
Xueshui Guo
Asuka Miwa
Takashi Iizuka
Katsuhisa Ikeda
Nagomi Kurebayashi
Shioko Ito-Kawashima
Kana Ogawa
Yoshinobu Sugitani
Tetsuo Noda
Hitomi Yamanaka
Miho Muraki
Source :
Journal of Clinical Investigation. 124:1598-1607
Publication Year :
2014
Publisher :
American Society for Clinical Investigation, 2014.

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.

Details

ISSN :
00219738
Volume :
124
Database :
OpenAIRE
Journal :
Journal of Clinical Investigation
Accession number :
edsair.doi.dedup.....c32156ab7f7818c7dc0f61ae6f5bf402
Full Text :
https://doi.org/10.1172/jci67621