Abstract
Primary congenital glaucoma (PCG) is an inherited blinding eye disease. The CYP1B1 gene was identified as a causal gene for PCG, and many mutations have been found, but no studies have focussed on the molecular epidemiology of CYP1B1 in Chinese populations. We aimed to explore the CYP1B1 mutation hotspots in Chinese PCG patients and the possible impact of these mutations on the protein structure and function. First, we performed a meta-analysis on seven datasets of Chinese populations and found L107V and R390H to be the most common CYP1B1 mutations with allele frequencies of 3.19% and 3.09%, respectively. Then, a series of bioinformatics tools were applied to determine the sequence conservative properties, model the 3D structures, and study the dynamics changes. L107 and R390 are highly conserved residues in close proximity to the hemoglobin-binding region and the active site cavity (ASC), respectively. The mutations changed the distribution of hydrogen bonds and the local electrostatic potential. Long-term molecular dynamics (MD) simulations demonstrated the destabilization of the mutant proteins, especially at the ASC, whose solvent-accessible surface areas (SASAs) were significantly decreased. Compared with the wild-type (WT) protein, the overall structures of the mutants are associated with subtle but significant changes, and the ASC seems to adopt such structures that are not able to perform the WT-like functionality. Therefore, L107V and R390H might be the most important pathogenic mutations in Chinese PCG patients.