通过序列、结构和分子动力学分析预测罕见神经遗传疾病神经鞘瘤病(神经肿瘤)中SMARCB1的高危临床错义变异。

IF 1.6 4区 医学 Q3 CLINICAL NEUROLOGY
Mitesh Patel, Reem Binsuwaidan, Malvi Surti, Nawaf Alshammari, Angum M M Ibrahim, Mohd Adnan
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引用次数: 0

摘要

SMARCB1基因编码SWI/SNF染色质修饰复合体的一个关键元件,该复合体通过修饰染色质结构在控制基因表达中发挥重要作用。SMARCB1的改变与几种神经功能障碍有关,包括神经鞘瘤病,这是一种以形成许多影响神经鞘的良性肿瘤为特征的疾病。本研究探讨了SMARCB1基因内的非同义单核苷酸多态性(nsSNPs)对其蛋白结构和功能的影响。我们利用基于序列和面向结构的预测模型,然后通过分子动力学模拟来研究它们对蛋白质稳定性和动态行为的影响。该研究主要关注三个关键突变:R60S、R190W和I237M。R190W突变尤为显著,由于疏水相互作用增强,导致蛋白质致密性和稳定性增加,尽管构象灵活性降低。R60S突变与蛋白质结构的不稳定,增加溶剂暴露和降低氢键稳定性有关,可能损害蛋白质的功能。I237M突变的影响相对轻微,仅在蛋白质动力学中观察到细微的变化。这些发现强调了不同的nssnp对SMARCB1的不同影响,可能导致各种病理,包括神经鞘瘤病和其他相关疾病。这项研究强调了额外的实验测试的必要性,以证实这些计算结果,并获得对这些突变导致疾病的分子过程的更深入的理解。目前的综合方法提供了关于SMARCB1结构和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提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Predicting high-risk clinical missense variants of SMARCB1 in rare neurogenetic disorder schwannomatosis (nerve tumor) through sequence, structure, and molecular dynamics analyses.

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.

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来源期刊
Neurogenetics
Neurogenetics 医学-临床神经学
CiteScore
3.90
自引率
0.00%
发文量
24
审稿时长
6 months
期刊介绍: Neurogenetics publishes findings that contribute to a better understanding of the genetic basis of normal and abnormal function of the nervous system. Neurogenetic disorders are the main focus of the journal. Neurogenetics therefore includes findings in humans and other organisms that help understand neurological disease mechanisms and publishes papers from many different fields such as biophysics, cell biology, human genetics, neuroanatomy, neurochemistry, neurology, neuropathology, neurosurgery and psychiatry. All papers submitted to Neurogenetics should be of sufficient immediate importance to justify urgent publication. They should present new scientific results. Data merely confirming previously published findings are not acceptable.
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