血小板生成素受体(MPL)基因是造血的关键调节因子,其结构或功能的任何改变都可能导致一系列血液病。MPL中的非同义单核苷酸多态性(nsSNPs)有可能破坏正常的蛋白质功能,促使我们调查最有害的MPLSNP以及影响蛋白质-蛋白质相互作用的相关结构变化。我们采用了一套全面的生物信息学工具,包括PredictSNP,InterPro,ConSurf,I-Mutant2.0,MUpro,Musitedeep,希望项目,STRING,RegulomeDB,Mutpred2,CScape,和CScape体细胞,分析MPL基因内的635个nsSNP。在分析的nsSNP中,PredictedSNP鉴定28为显著致病性,揭示了MPL中的三个关键功能域。这些nsSNPs中有十个表现出很高的保护分数,表明对蛋白质结构和功能的潜在影响,而发现14种损害MPL蛋白稳定性。虽然最有害的nsSNP并不直接影响翻译后修饰位点,13具有实质上改变蛋白质的物理化学性质的能力。一些突变对血液功能至关重要的蛋白质-蛋白质相互作用构成了风险,和三个非编码区nsSNPs显示出显著的调节潜能,对造血有潜在影响。此外,评估的21个nsSNP中的13个被Mutpred2分类为高风险致病变体。值得注意的是,氨基酸改变,如C291S,T293N,D295G,和W435C,虽然对蛋白质的稳定性和功能有影响,被认为是非致癌的“乘客”突变。我们的研究强调了错义nsSNPs对MPL蛋白结构和功能的实质性影响。鉴于MPL在造血中的核心作用,这些突变可以显著破坏血液学过程,可能导致各种疾病。鉴定的高风险致病性nsSNP可能有望作为血液病的潜在生物标志物或治疗靶标。本研究为进一步研究MPL基因在血液健康和疾病领域的作用奠定了基础。
The thrombopoietin receptor (MPL) gene is a critical regulator of hematopoiesis, and any alterations in its structure or function can result in a range of hematological disorders. Non-synonymous single nucleotide polymorphisms (nsSNPs) in MPL have the potential to disrupt normal protein function, prompting our investigation into the most deleterious MPL SNPs and the associated structural changes affecting protein-protein interactions. We employed a comprehensive suite of bioinformatics tools, including PredictSNP, InterPro, ConSurf, I-Mutant2.0, MUpro, Musitedeep, Project HOPE, STRING, RegulomeDB, Mutpred2, CScape, and CScape Somatic, to analyze 635 nsSNPs within the MPL gene. Among the analyzed nsSNPs, PredictSNP identified 28 as significantly pathogenic, revealing three critical functional domains within MPL. Ten of these nsSNPs exhibited high conservation scores, indicating potential effects on protein structure and function, while 14 were found to compromise MPL protein stability. Although the most harmful nsSNPs did not directly impact post-translational modification sites, 13 had the capacity to substantially alter the protein\'s physicochemical properties. Some mutations posed a risk to vital protein-protein interactions crucial for hematological functions, and three non-coding region nsSNPs displayed significant regulatory potential with potential implications for hematopoiesis. Furthermore, 13 out of 21 nsSNPs evaluated were classified as high-risk pathogenic variants by Mutpred2. Notably, amino acid alterations such as C291S, T293N, D295G, and W435C, while impactful on protein stability and function, were deemed non-oncogenic \"passenger\" mutations. Our study underscores the substantial impact of missense nsSNPs on MPL protein structure and function. Given MPL\'s central role in hematopoiesis, these mutations can significantly disrupt hematological processes, potentially leading to a variety of disorders. The identified high-risk pathogenic nsSNPs may hold promise as potential biomarkers or therapeutic targets for hematological diseases. This research lays the foundation for future investigations into the MPL gene\'s role in the realm of hematological health and diseases.