Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss.

Connexins (Cx) form gap junctions that allow the exchange of small metabolites and ions. In the inner ear, Cx26 is the major gap junction protein and mutations in the Cx26-encoding gene, GJB2, are the most frequent cause of autosomal recessive non-syndromic hearing loss (DFNB1). We have functionally analyzed five Cx26 mutations associated with DFNB1, comprising the following single amino-acid substitutions: T8M, R143W, V153I, N206S and L214P. Coupling of cells expressing wild-type or mutant Cx26 was measured in the paired Xenopus oocyte assay. We found that the R143W, V153I and L214P mutations were unable to form functional channels. In contrast, the T8M and N206S mutants did electrically couple cells, though their voltage gating properties were different from wild-type Cx26 channels. The electrical coupling of oocytes expressing the T8M and N206S mutants suggest that these channels may retain high permeability to potassium ions. Therefore, deafness associated with Cx26 mutations may not only depend on reduced potassium re-circulation in the inner ear. Instead, abnormalities in the exchange of other metabolites through the cochlear gap junction network may also produce deafness.