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在FZD8基因中编码和非编码SNP对与瘤发生相关的结构和功能变化的影响:一个多方面的计算方法
Amalesh Mondal1, Debarati Paul2, Tithi Mondal3
1Department of Physiology, Katwa College, Katwa, Purba Bardhaman, West Bengal, 713130, India.
这项研究确定了高风险的FZD8基因SNP影响蛋白质结构和功能,可能导致瘤发生. 这些发现提供了有关癌症发展的见解,以及FZD8相关疾病的潜在治疗点.
科学领域:
- 遗传学 是一个遗传学.
- 生物信息学是一种生物信息学.
- 分子生物学分子生物学
背景情况:
- Frizzled-8 (FZD8) 是一种与G蛋白结合的受体,对Wnt信号传递至关重要,参与细胞分化和发育.
- 异常的Wnt/FZD信号传递有助于瘤发生,但FZD8遗传变异的影响仍然在很大程度上未被探索.
研究的目的:
- 通过计算分析FZD8基因中的单核酸多态 (SNPs),以了解它们对瘤发生的结构和功能影响.
- 确定有害的FZD8SNP并评估它们对蛋白质功能,稳定性和Wnt1结合的影响.
主要方法:
- 在FZD8基因中对450个CDS,109个3'UTR和390个5'UTRSNP进行生物信息分析.
- 预测SNP的结构和功能后果,包括对翻译后修改和mRNA稳定性的影响.
- 分子动力学 (MD) 模拟以评估nsSNP对Wnt1-FZD8复合体稳定性的影响.
主要成果:
- 确定了10个高度有害的非同义SNP (nsSNP),其中6个位于Wnt1结合区域.
- 预测的nsSNP会影响翻译后修饰和mRNA稳定性,而P120Q会导致显著的结构变化.
- 模拟MD表明变异Wnt1-FZD8复合物的稳定性降低,特别是P74L和A119E.
- 已确定SNP可能通过AGO2,E2F6和miRNA途径影响基因沉默.
- 在瘤中观察到差异性的FZD8表达,与较差的存活率相关,并被确定为胃癌,多发性髓瘤和子宫癌中的生物标志物.
结论:
- 计算优先级的高风险FZD8SNP具有与瘤发生相关的显著结构和功能影响.
- 这些已识别的SNP可以作为基于人群的遗传研究和未来针对FZD8相关癌症的药物开发的目标.
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