Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.

Gap-junctional channels (connexin oligomers) are large-diameter aqueous pores formed by head-to-head association of two gap-junctional hemichannels, one from each of the adjacent cells. Profound hearing loss of genetic origin is common, and mutations of connexin 26 (Cx26) are the most frequent cause of this disorder. The Cx26 R75W mutant has been associated with disruption of cell-to-cell communication and profound hearing loss, but the mechanism of the gap-junctional defect is unknown. Here, we show that Cx26 R75W forms gap-junctional hemichannels that display altered voltage dependency and reduced permeability, and which cannot form functional gap-junctional channels between neighboring cells. The R75W phenotype is dominant at the gap-junction channel but not at the hemichannel level. Therefore, the absence of gap-junctional communication caused by R75W expression is due to defective gap-junction formation by functional hemichannels.