α-crystallins are small heat shock proteins, function as molecular chaperones to inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of CRYAA are associated with protein aggregation and cataract occurance. One possible mechanism causing cataract is that endoplasmic reticulum stress (ERS) induces unfolded protein response (UPR) and eventually leads to apoptosis. However, the underlying pathogenic mechanism has not been explored. Here, we successfully constructed cataract-causing mutant CRYAA (Y118D) related mouse model and the lens of CRYAA-Y118D mutant mouse showed severe posterior rupture, abnormal morphological changes and aberrant arrangement in crystallin fibers. Histological results were consistent with the clinical pathological characteristics. Further, we explored pathogenic factors in cataract development process through transcriptome analysis. Key pathway analysis showed that up-regulated genes in CRYAA-Y118D mutant mouse were implicated in ERS-UPR pathway. The findings of this study show that prolonged activation of UPR pathway and severe stress response causes proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mouse.