Cataract-causing mutation R48C increases γA-crystallin susceptibility to oxidative stress and ultraviolet radiation

Among all congenital cataracts caused by genetic mutations, approximately half are caused by a mutation in crystallin genes, and accounts the leading cause of blindness in children globally. In this study, we investigated the underlying molecular mechanism of R48C mutation (c.142C > T; p.[Arg48Cys]) of gamma A-crystallin in a Mexican-Mestizo descent family causing congenital cataracts. We purified gamma A-crystallin wild-type (WT) and R48C mutant and compared their structural characteristics and biophysical properties by Spectroscopic experiments and environmental stress (oxidative stress, ultraviolet irradiation, pH disorders, thermal shock, or chemical denaturation). The R48C mutant did not affect the secondary and tertiary structure of monomer gamma A-crystallin, nor did it affect its stability to heat shock and chemicals. However, the R48C mutant destroys the oxidative stability of gamma A-crystallin, which makes the protein more prone to aggregation and precipitation under oxidative conditions. These might be the pathogenesis of gamma A-crystallin R48C mutant related to congenital cataract and help to develop anti-cataract strategies from the perspective of gamma A-crystallin.

Automated summary

This study investigated the molecular mechanism of the R48C mutation of gamma A-crystallin in a Mexican-Mestizo descent family causing congenital cataracts. The R48C mutation did not affect the secondary and tertiary structure of the protein, but it did disrupt its oxidative stability, leading to increased aggregation and precipitation under oxidative conditions, potentially contributing to the pathogenesis of congenital cataracts related to this mutation.