Comprehensive structure-function analysis of causative variants in retinal pigment epithelium specific 65 kDa protein associated Leber Congenital Amaurosis

摘要

A recent study published to screen in 187 families with Leber Congenital Amaurosis (LCA) by Zilin Zhong in 2019. There are seven novel variants were identified in which was associated with LCA, but among only five were missense mutations [(c.124C > T, p.(Leu42Phe), c.149T > C, p. (Phe50Ser), c.340A > C, p.(Asn114His), c.425A > G, p.(Asp142Gly) and c.1399C > G, p.(Pro467Ala)] in the Chinese population and potentially facilitates its clinical implementation. Further in-continuation of this study to the target of five novel missense mutations were the analysis of both structural and functional impact by the molecular dynamics and simulation. The result of five missense mutations might in critical structural alterations of RPE65 protein, disrupt its membrane association or rescue the activity of enzyme due to thermodynamics stability, and for this reason impair its isomerohydrolase activity, resulting in retinal dystrophy. These observations suggest that the reduced protein stability and altered subcellular localization of RPE65 might signify a mechanism for these mutations to lead to vision loss in LCA patients.