Mutations in GJA8 are associated with hereditary autosomal dominant and recessive cataract formation. In this study, a novel insert mutation in GJA8 was identified in a Chinese congenital cataract family and cosegregated with the disease in this pedigree. This insert mutation introduces five additional amino acid residues YAVHY after histidine at the 95 site (p.H95_A96insYAVHY) within the second transmembrane (TM2) domain of Cx50 protein (Cx50-insert). Ectopic expression of Cx50-insert protein impairs the hemichannel functions and gap junction activity compared to wild-type Cx50 protein in human lens epithelial cells. Cx50-insert proteins were mislocated from cytoplasmic membrane to endoplasmic reticulum and lysosome. In mouse lens tissue, our results showed that Cx50 predominant expresses in epithelial cells and fiber cells at the transition zone of lens hinting its roles in lens differentiation. Taken together, these data suggest that the novel insert mutation in the TM2 domain of Cx50 protein, which impairs its trafficking to the cell membrane and gap-junction function, is associated with the cataract formation in this Chinese pedigree.
Keywords: Cx50; cataract; hemichannel function; insert mutation; membrane localization.