Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43

J Invest Dermatol. 2015 May;135(5):1338-1347. doi: 10.1038/jid.2015.20. Epub 2015 Jan 27.


Mutations in Cx26 gene are found in most cases of human genetic deafness. Some mutations produce syndromic deafness associated with skin disorders, like the Keratitis-Ichthyosis-Deafness syndrome (KID). Because in the human skin connexin 26 (Cx26) is co-expressed with other connexins, like Cx43 and Cx30, and as the KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins. Indeed, some Cx26 syndromic mutations showed gap junction dominant negative effect when co-expressed with wild-type connexins, including Cx26 and Cx43. The nature of these interactions and the consequences on hemichannels and gap junction channel (GJC) functions remain unknown. In this study, we demonstrate that syndromic mutations, at the N terminus segment of Cx26, change connexin oligomerization compatibility, allowing aberrant interactions with Cx43. Strikingly, heteromeric oligomer formed by Cx43/Cx26 (syndromic mutants) shows exacerbated hemichannel activity but nonfunctional GJCs; this also occurs for those Cx26 KID mutants that do not show functional homomeric hemichannels. Heterologous expression of these hyperactive heteromeric hemichannels increases cell membrane permeability, favoring ATP release and Ca(2+) overload. The functional paradox produced by oligomerization of Cx43 and Cx26 KID mutants could underlie the severe syndromic phenotype in human skin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Calcium / metabolism
  • Cell Membrane Permeability / physiology
  • Connexin 26
  • Connexin 43 / genetics*
  • Connexin 43 / physiology
  • Connexins / genetics*
  • Connexins / physiology
  • Deafness / genetics*
  • Deafness / physiopathology
  • Gap Junctions / genetics
  • Gap Junctions / physiology*
  • Genotype
  • HeLa Cells
  • Humans
  • Ichthyosis / genetics*
  • Ichthyosis / physiopathology
  • Ion Channels / genetics
  • Ion Channels / physiology*
  • Keratitis / genetics*
  • Keratitis / physiopathology
  • Mutation / genetics*
  • Phenotype


  • Connexin 43
  • Connexins
  • GJB2 protein, human
  • Ion Channels
  • Connexin 26
  • Adenosine Triphosphate
  • Calcium

Supplementary concepts

  • Keratitis, Ichthyosis, and Deafness (KID) Syndrome