Patel Mitesh, Binsuwaidan Reem, Surti Malvi, Alshammari Nawaf, Ibrahim Angum M M, Adnan Mohd
Research and Development Cell (RDC), Parul University, Waghodia, Vadodara, Gujarat, 391760, India.
Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Waghodia, Vadodara, Gujarat, 391760, India.
Neurogenetics. 2025 Feb 20;26(1):31. doi: 10.1007/s10048-025-00812-z.
The SMARCB1 gene codes for a key element of the SWI/SNF chromatin-modifying complex, which plays a vital role in controlling gene expression by modifying chromatin architecture. Alterations in SMARCB1 have been linked to several neurological disabilities, including schwannomatosis, a condition marked by the formation of numerous benign tumors affecting the nerve sheaths. Present study explore the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) within the SMARCB1 gene on its protein structure and functionality. We utilized both sequence-based and structure-oriented predictive models, followed by molecular dynamics simulations to examine their influence on the stability of protein and dynamic behaviour. The study focused on three key mutations: R60S, R190W, and I237M. The R190W mutation emerged as particularly significant, leading to increased protein compactness and stability due to enhanced hydrophobic interactions, although conformational flexibility was reduced. The R60S mutation was associated with destabilization of the protein structure, increasing solvent exposure and reducing hydrogen bond stability, potentially impairing the protein's function. The I237M mutation had a relatively mild impact, with only subtle changes observed in protein dynamics. These findings highlight the diverse impacts of different nsSNPs on SMARCB1, with the potential to contribute to various pathologies, including Schwannomatosis and other related disorders. This study highlights the necessity for additional experimental testing to confirm these computational findings and gain a deeper understanding of the molecular processes through which these mutations contribute to disease. The present comprehensive approach provides significant knowledge regarding the connection between SMARCB1 structure and function, providing the groundwork for potential therapeutic strategies targeting these key mutations.
SMARCB1基因编码SWI/SNF染色质修饰复合物的一个关键元件，该复合物通过修饰染色质结构在控制基因表达中发挥至关重要的作用。SMARCB1的改变与多种神经功能障碍有关，包括神经鞘瘤病，这是一种以形成影响神经鞘的众多良性肿瘤为特征的疾病。本研究探讨了SMARCB1基因内非同义单核苷酸多态性（nsSNPs）对其蛋白质结构和功能的影响。我们使用了基于序列和面向结构的预测模型，随后进行分子动力学模拟，以研究它们对蛋白质稳定性和动态行为的影响。该研究聚焦于三个关键突变：R60S、R190W和I237M。R190W突变显得尤为显著，由于疏水相互作用增强，导致蛋白质紧凑性和稳定性增加，尽管构象灵活性降低。R60S突变与蛋白质结构的不稳定有关，增加了溶剂暴露并降低了氢键稳定性，可能损害蛋白质的功能。I237M突变的影响相对较小，在蛋白质动力学中仅观察到细微变化。这些发现突出了不同nsSNPs对SMARCB1的多样影响，有可能导致包括神经鞘瘤病和其他相关疾病在内的各种病理状况。本研究强调了进行额外实验测试以证实这些计算结果并更深入了解这些突变导致疾病的分子过程的必要性。目前的综合方法提供了关于SMARCB1结构与功能之间联系的重要知识，为针对这些关键突变的潜在治疗策略奠定了基础。
