Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

As small heat shock proteins, alpha-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of beta/gamma-crystallins. Genetic mutations of CRYAA are associated with protein aggregation and cataract occurrence. One possible process underlying cataract formation is that endoplasmic reticulum stress (ERS) induces the unfolded protein response (UPR), leading to apoptosis. However, the pathogenic mechanism related to this remains unexplored. Here, we successfully constructed a cataract-causing CRYAA (Y118D) mutant mouse model, in which the lenses of the CRYAA-Y118D mutant mice showed severe posterior rupture, abnormal morphological changes, and aberrant arrangement of crystallin fibers. Histological analysis was consistent with the clinical pathological characteristics. We also explored the pathogenic factors involved in cataract development through transcriptome analysis. In addition, based on key pathway analysis, up-regulated genes in CRYAA-Y118D mutant mice were implicated in the ERS-UPR pathway. This study showed that prolonged activation of the UPR pathway and severe stress response can cause proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mice.

Automated summary

This study revealed that the up-regulated genes in CRYAA-Y118D mutant mice were implicated in the endoplasmic reticulum stress (ERS) - unfolded protein response (UPR) pathway, leading to proteotoxicity and cell death. The CRYAA-Y118D mutant mice showed severe cataract-related phenotypes and aberrant arrangements of crystallin fibers, providing insights into the pathogenic mechanisms underlying cataract formation.