Mutations in Connexin-encoding genes

Gap junctions formed of connexin46 (Cx46) and connexin50 (Cx50) facilitate lens function and survival. Mutations of the connexin-encoding genes (GJA3 and GJA8) have been linked to inherited cataracts. We expressed these mutants in vitro to elucidate abnormalities that contribute to cataractogenesis. Most of the mutants reduce intercellular communication due to alterations of channel function or impaired connexin synthesis/assembly/stability. One unusual mutant (Cx50P88S) forms cytoplasmic accumulations that may act as light scattering particles. Another unusual mutant (Cx50G46V) exhibits increased hemichannel function that may cause cell injury and death. We have studied mice expressing two different connexin mutants (Cx50D47A and Cx46 fs380) that mimic cataract-linked human mutations. Both mouse lines develop cataracts (although with different time courses) and have reduced connexin levels (mutant and co-expressed wild type) likely due to protein degradation. Our studies suggest that reduction of intercellular communication is a common feature that contributes to connexin mutant-linked cataractogenesis, but individual mutants cause additional abnormalities that contribute to differences in phenotypes.