Nezamuldeen Leena, Jafri Mohsin Saleet
School of Systems Biology, George Mason University, Fairfax, VA 22030, USA.
King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Biology (Basel). 2024 Aug 10;13(8):606. doi: 10.3390/biology13080606.
Cellular molecules interact with one another in a structured manner, defining a regulatory network topology that describes cellular mechanisms. Genetic mutations alter these networks' pathways, generating complex disorders such as autism spectrum disorder (ASD). Boolean models have assisted in understanding biological system dynamics since Kauffman's 1969 discovery, and various analytical tools for regulatory networks have been developed. This study examined the protein-protein interaction network created in our previous publication of four ASD patients using the SPIDDOR R package, a Boolean model-based method. The aim is to examine how patients' genetic variations in INTS6L, USP9X, RSK4, FGF5, FLNA, SUMF1, and IDS affect mTOR and Wnt cell signaling convergence. The Boolean network analysis revealed abnormal activation levels of essential proteins such as β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD. These proteins affect gene expression, translation, cell adhesion, shape, and migration. Patients 1 and 2 showed consistent patterns of increased β-catenin activity and decreased MTORC1, RPS6, and eIF4E activity. However, patient 2 had an independent decrease in Cadherin and SMAD activity due to the FLNA mutation. Patients 3 and 4 have an abnormal activation of the mTOR pathway, which includes the MTORC1, RPS6, and eIF4E genes. The shared mTOR pathway behavior in these patients is explained by a shared mutation in two closely related proteins (SUMF1 and IDS). Diverse activities in β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD contributed to the reported phenotype in these individuals. Furthermore, it unveiled the potential therapeutic options that could be suggested to these individuals.
细胞分子以一种结构化的方式相互作用，定义了一个描述细胞机制的调控网络拓扑结构。基因突变会改变这些网络的通路，引发诸如自闭症谱系障碍（ASD）等复杂疾病。自1969年考夫曼发现以来，布尔模型一直有助于理解生物系统动力学，并且已经开发出了各种用于调控网络的分析工具。本研究使用基于布尔模型的方法SPIDDOR R包，检查了我们之前发表的四位ASD患者所构建的蛋白质-蛋白质相互作用网络。目的是研究INTS6L、USP9X、RSK4、FGF5、FLNA、SUMF1和IDS患者的基因变异如何影响mTOR和Wnt细胞信号转导汇聚。布尔网络分析揭示了β-连环蛋白、MTORC1、RPS6、eIF4E、钙黏着蛋白和SMAD等关键蛋白的异常激活水平。这些蛋白影响基因表达、翻译、细胞黏附、形状和迁移。患者1和患者2表现出β-连环蛋白活性增加以及MTORC1、RPS6和eIF4E活性降低的一致模式。然而，由于FLNA突变，患者2的钙黏着蛋白和SMAD活性独立降低。患者3和患者4的mTOR通路存在异常激活，其中包括MTORC1、RPS6和eIF4E基因。这些患者中mTOR通路的共同行为可由两种密切相关蛋白（SUMF1和IDS）中的共同突变来解释。β-连环蛋白、MTORC1、RPS6、eIF4E、钙黏着蛋白和SMAD的不同活性导致了这些个体所报告的表型。此外，它还揭示了可以向这些个体建议的潜在治疗选择。
