Awan Muhammad, Johnson Eric B
Research, Alabama College of Osteopathic Medicine, Dothan, USA.
Anatomy and Molecular Medicine, Alabama College of Osteopathic Medicine, Dothan, USA.
Cureus. 2025 May 2;17(5):e83372. doi: 10.7759/cureus.83372. eCollection 2025 May.
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.
引言 原发性开角型青光眼是一种慢性、多因素的视神经病变。虽然该疾病的确切病因尚不清楚，但肌纤蛋白（尤其是嗅觉介质（OLF）结构域内）的突变与眼压升高和开角型青光眼的发生有关。然而，肌纤蛋白仍有许多意义不明确的变异体，其致病作用未知。在本研究中，我们对肌纤蛋白OLF结构域第414位谷氨酸到赖氨酸的替换（E414K）进行了模拟分析，以探讨该变异体在原发性开角型青光眼发病机制中的潜在作用。
方法 对天然和变异的肌纤蛋白进行20纳秒的分子动力学模拟。通过均方根偏差和动态交叉相关矩阵分析研究结构变化。利用预测程序了解肌纤蛋白的进化模式，并评估E414K替换的致病性。
结果 均方根偏差分析显示，天然和变异的肌纤蛋白之间没有显著的结构差异。虽然动态交叉相关矩阵热图表明OLF结构域中特定残基之间的相互作用发生了改变，但这些变化不足以破坏蛋白质的功能或结构。肌纤蛋白的进化分析表明，第414位的谷氨酸残基在不同物种间存在差异因此，该位点的突变不太可能是有害的。PredictSNP（由捷克布尔诺马萨里克大学的Jiri Damborsky及其同事开发）进一步支持了E414K突变的良性性质。
结论 我们的研究得出结论，E414K替换是一种良性突变，不太可能导致OLF结构域不稳定，也不会导致原发性开角型青光眼的发病机制。虽然我们的研究范围有限，但强调了进一步研究肌纤蛋白变异体以识别致病突变的重要性。对肌纤蛋白变异体的持续分析可能会增进对原发性开角型青光眼的理解和治疗。
