Abstract：
γS-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 γS-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 γS-crystallin (c.53G > A; p. G18D) with progressive cortical and sutural congenital cataracts in one Chinese family. In this study, we purified the γS-crystallin wildtype and mutant proteins to investigate the effects of the G18D mutation on the structural stability of γS-crystallin. The results showed that there were tertiary structural differences between the wild-type γS-crystallin and the G18D variant. The mutation significantly impaired the stability of γS-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.
摘要：
γS-晶状体蛋白在胚胎核区特别丰富，对维持晶状体透明度和光学性质至关重要。晶状体蛋白基因突变是导致先天性遗传性白内障的主要因素,这是儿童视力障碍的主要原因。据报道，位于γS-晶状体蛋白第18位氨基酸甘氨酸中的一些突变与先天性白内障有关。然而,致病机制尚未阐明。有趣的是,我们先前在一个中国家庭中发现了一种新的γS晶状体蛋白变体（c.53G>A；p。G18D），患有进行性皮质和缝合性先天性白内障。在这项研究中,我们纯化了γS-晶状体蛋白野生型和突变蛋白，以研究G18D突变对γS-晶状体蛋白结构稳定性的影响。结果表明，野生型γS-晶状体蛋白和G18D变体之间存在三级结构差异。该突变显着损害了γS-晶状体蛋白在环境胁迫下的稳定性并促进了聚集。此外，分子动力学（MD）模拟表明，突变改变了H键和表面静电势。在环境胁迫下，稳定性显着降低以及聚集趋势增加可能是G18D突变引起的白内障的主要致病因素。
