Effect of Myocilin E414K Variant on the Pathogenesis of Primary Open-Angle Glaucoma.

Introduction Primary open-angle glaucoma is a chronic, multifactorial condition of optic neuropathy. While the exact cause of the disease is not well understood, mutations in the protein myocilin, particularly within the olfactomedin (OLF) domain, have been associated with the development of increased intraocular pressure and open-angle glaucoma. However, many variants of uncertain significance of myocilin remain, with unknown pathogenic roles. In this study, we performed a simulated analysis of a glutamate-to-lysine substitution at position 414 (E414K) in the OLF domain of myocilin to explore the potential role of the variant in the pathogenesis of primary open-angle glaucoma. Methods The native and variant myocilin proteins were run through 20-nanosecond molecular dynamics simulations. Structural changes were studied with root-mean-square deviation and dynamic cross-correlation matrix analyses. Predictive programs were utilized to understand the evolutionary patterns of myocilin and estimate the pathogenicity of the E414K substitution. Results The root-mean-square deviation analysis revealed no significant structural differences between the native and variant myocilin proteins. While the dynamic cross-correlation matrix heat map suggested alterations in interactions between specific residues in the OLF domain, these changes were not significant enough to disrupt protein function or structure. Evolutionary analysis of myocilin demonstrated that the glutamate residue at position 414 was variable across species, and therefore, mutations at this site are unlikely to be deleterious. PredictSNP (developed by Jiri Damborsky and colleagues at Masaryk University, Brno, Czech Republic) further supported the benign nature of the E414K mutation. Conclusion Our study concluded that the E414K substitution is a benign mutation that is unlikely to cause instability of the OLF domain and contribute to the pathogenesis of primary open-angle glaucoma. While limited in scope, our research underscores the importance of further studies into myocilin variants to identify pathogenic mutations. Continued analysis of myocilin variants may advance the understanding and treatment of primary open-angle glaucoma.