Insight into Pathogenic Mechanism Underlying the Hereditary Cataract Caused by B2-G149V Mutation

Congenital cataracts account for approximately 5-20% of childhood blindness worldwide and 22-30% of childhood blindness in developing countries. Genetic disorders are the primary cause of congenital cataracts. In this work, we investigated the underlying molecular mechanism of G149V point missense mutation in beta B2-crystallin, which was first identified in a three-generation Chinese family with two affected members diagnosed with congenital cataracts. Spectroscopic experiments were performed to determine the structural differences between the wild type (WT) and the G149V mutant of beta B2-crystallin. The results showed that the G149V mutation significantly changed the secondary and tertiary structure of beta B2-crystallin. The polarity of the tryptophan microenvironment and the hydrophobicity of the mutant protein increased. The G149V mutation made the protein structure loose and the interaction between oligomers was reduced, which decreased the stability of the protein. Furthermore, we compared beta B2-crystallin WT and the G149V mutant with their biophysical properties under environmental stress. We found that the G149V mutation makes beta B2-crystallin more sensitive to environmental stresses (oxidative stress, UV irradiation, and heat shock) and more likely to aggregate and form precipitation. These features might be important to the pathogenesis of beta B2-crystallin G149V mutant related to congenital cataracts.