Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expresion

Eva Thönnissen, Raquel Rabionet, Maria Lourdes Arbonès, Xavier Estivill, Klaus Willecke, Thomas Ott

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Abstract

Mutations in the connexin26 (GJB2) gene account for about half of inherited non-syndromic deafness cases in Western countries. The connexin26 protein is a subunit of gap junctions that form a network of intercellular communication among supporting cells and fibrocytes in the mammalian inner ear. Here we describe functional implications of mutations in the coding region of connexin26 genes (M1V, M34T, L90P, R127H, F161S, P173R, and R184P), identified in patients and stably transfected in human HeLa cells. While all mutated connexin26 cDNAs were transcribed, only M34T, L90P, R127H, F161S, and R184P were translated in HeLa cells. Analysis of indirect immunofluorescence showed membranous localization, strong for M34T, L90P, R127H, and very weak for F161S, but no signal corresponding to M1V, P173R and R184P. Tracer coupling experiments revealed diffusion of microinjected neurobiotin into neighbouring cells in the case of M34T and R127H, whereas M1V, L90P, F161S, P173R and R184P mutants did not show intercellular coupling. The results of oligomerisation studies suggested a partly disturbed assembly of hemichannels in M34T and L90P mutants but complete absence of hemichannel formation in the R184P mutant. The R127H mutation did not affect channel formation and is likely to represent a polymorphism. Our results show that mutations in the connexin26 gene can affect gap junctional intercellular communication at the level of protein translation, trafficking or assembly of hemichannels.

Original languageEnglish
Pages (from-to)190-197
Number of pages8
JournalHuman Genetics
Volume111
Issue number2
DOIs
Publication statusPublished - 1 Aug 2002

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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