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.
Highlights
Primary congenital glaucoma (PCG) is an eye disease that affects children between the ages of birth and 3 years [1]
Genetic linkage studies have indicated that PCG is a heterogeneous disease that is mainly mapped on to the locus GLC3A and the CYP1B1 gene, which harbors more than 80 mutations in PCG amongst different racial groups [29,30]
Since the relationship was apparent between the CYP1B1 gene variants and the eye angle tissue histology or the clinical phenotype, PCG treatment programs could be established according to the mutation screening
Summary
Primary congenital glaucoma (PCG) is an eye disease that affects children between the ages of birth and 3 years [1]. 50% of patients show symptoms at birth, and 80% of patients are confirmed at 1 year. 65% of patients are male and 70% of patients have symptoms in both the eyes [2]. The Gypsy population in Slovakia has the highest incidence of 1:1250, which might be due to the higher incidence of consanguinity. This point of view is further supported by the fact that the consanguinity rate in the parents of PCG patients is significantly higher than those of secondary congenital glaucoma patients [6]
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