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Mutations in connexin 26 hemichannels are the most common cause of congenital sensorineural hearing loss. Sanchez et al. investigate two mutations with disparate effects, N14K and N14Y, and find that the open state is stabilized in N14K channels.

Mutations in the gene (GJA1) encoding connexin43 (Cx43) are responsible for several rare genetic disorders, including non-syndromic skin-limited diseases. Here we used two different functional expression systems to characterize three Cx43 mutations linked to palmoplantar keratoderma and congenital alopecia-1, erythrokeratodermia variabilis et progressiva, or inflammatory linear verrucous epidermal nevus. In HeLa cells and Xenopus oocytes, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D all formed functional gap junction channels with the same efficiency as wild-type Cx43, with normal voltage gating and a unitary conductance of ~110 pS. In HeLa cells, all three mutations also localized to regions of cell-cell contact and displayed a punctate staining pattern. In addition, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D significantly increase membrane current flow through formation of active hemichannels, a novel activity that was not displayed by wild-type Cx43. The increased membrane current was inhibited by either 2 mM calcium, or 5 µM gadolinium, mediated by hemichannels with a unitary conductance of ~250 pS, and was not due to elevated mutant protein expression. The three Cx43 mutations all showed the same gain of function activity, suggesting that augmented hemichannel activity could play a role in skin-limited diseases caused by human Cx43 mutations.

Background: Aberrantly functioning Cx26 hemichannels are a common feature of GJB2 mutations causing syndromic deafness. Results: pH and Zn 2ϩ , factors that inhibit hemichannels, are less effective in the A40V KID syndrome mutant. Conclusion: Impaired inhibition by pH and Zn 2ϩ can contribute to the pathogenesis of KID syndrome. Significance: Data provide new insights into Cx26 hemichannel function and possible contributions to tissue function.