Lenses from Connexin50 Mutant Mice Exhibit the Unfolded Protein Response

Abstract

Cataract is the leading cause of blindness worldwide. Although the majority of cataracts are age‐related, they may also be caused by heritable mutations. In humans as well as mice, congenital cataract occurs in Connexin50 (Cx50) mutants although the cataract phenotypes are more severe than that observed in Cx50 null mice. We hypothesized that when cells attempt to make Cx50 from a mutated gene, the resulting protein does not fold properly, inducing a cell‐stress mechanism called the Unfolded Protein Response, UPR. We investigated this in mice harboring two different Cx50 mutations, Cx50S50P/S50P and Cx50G22R/G22R, that both exhibit similar lens phenotypes including microphthalmia, unorganized fiber cell structure, and cataract. We found a noticeable upregulation of the expression of the molecular folding chaperone BiP in mutant lenses after E15.5 in addition to an upregulation of XBP‐1 gene expression and unconventional splicing indicative of the activation of the UPR sensor IRE1. These data further support our prior work suggesting that UPR can contribute to lens phenotypes due to mutations in genes whose products must transit the secretory pathway. Supported by the Howard Hughes Medical Institute, Fight for Sight, and the National Eye Institute.