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Am J Physiol Cell Physiol 2013 Jun 15;30412:C1150-8. doi: 10.1152/ajpcell.00374.2012.
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The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity.

Mhaske PV , Levit NA , Li L , Wang HZ , Lee JR , Shuja Z , Brink PR , White TW .

Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome.

PubMed ID: 23447037
PMC ID: PMC3680649
Article link: Am J Physiol Cell Physiol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: gjb2 kif22

References [+] :
Barrio, Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage. 1991, Pubmed, Xenbase