The 18th amino acid glycine plays an essential role in maintaining the structural stabilities of ?S-crystallin linking with congenital cataract

?S-crystallin is particularly rich in the embryonic nuclear region and is crucial to the maintenance of lens transparency and optical properties. Gene mutations in crystallin are the main factors leading to congenital hereditary cataracts, which are a major cause of visual impairment in children. Some mutations located in the 18th amino acid glycine of ?S-crystallin were reported to be linking with congenital cataracts. However, the pathogenic mechanism has not been elucidated. Interestingly, we previously identified a novel variant of ?Scrystallin (c.53G > A; p. G18D) with progressive cortical and sutural congenital cataracts in one Chinese family. In this study, we purified the ?S-crystallin wildtype and mutant proteins to investigate the effects of the G18D mutation on the structural stability of ?S-crystallin. The results showed that there were tertiary structural differences between the wild-type ?S-crystallin and the G18D variant. The mutation significantly impaired the stability of ?S-crystallin under environmental stress and promoted aggregation. Furthermore, molecular dynamics (MD) simulations showed that the mutation altered H-bonding and surface electrostatic potential. Significantly decreased stability along with an increased tendency to aggregate under environmental stress may be the major pathogenic factors for cataracts induced by the G18D mutation.

Automated summary

This study found that a specific mutation in S-crystallin (G18D mutation) leads to congenital hereditary cataracts and the mutation affects the stability of S-crystallin and promotes aggregation. These findings are important for understanding the pathogenesis of congenital cataracts.