Arshad Sidra, Ishaque Irfan, Mumtaz Sidra, Rashid Muhammad Usman, Malkani Naila
Department of Zoology, GC University, Lahore, Pakistan.
Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), Lahore, Pakistan.
Biochem Genet. 2021 Dec;59(6):1506-1526. doi: 10.1007/s10528-021-10074-7. Epub 2021 May 4.
BReast CAncer gene 1 (BRCA1)-a tumor suppressor gene plays an important role in the DNA repair mechanism. Several BRCA1 variants perturb its structure and function, including synonymous and nonsynonymous single nucleotide polymorphisms (SNPs). In the present study, we performed in-silico analyses of nonsynonymous SNPs (nsSNPs) of the BRCA1 gene. In total, 122 nsSNPs were retrieved from the NCBI SNP database and in-silico analyses were performed using computational prediction tools: SIFT, PROVEAN, Mutation Taster, PolyPhen-2, MutPred, and ConSurf. Of these tools, SIFT, PROVEAN, and Mutation Taster predicted 61 out of 122 nsSNPs as "damaging", based on structural homology analysis. PolyPhen-2 classified 22 nsSNPs as "probably damaging". These nsSNPs were further analyzed by MutPred to predict basic molecular mechanisms of amino acid alteration. ConSurf analysis predicted eleven conserved amino acid residues with structural and functional consequences. We identified five amino acid residues in the RING finger domain (L22, C39, H41, C44, and C47) and two in the BRCT domain (P1771 and I1707) with the potential to deter the BRCA1 protein function. This study provides insights into the effect of nsSNPs and amino acid substitutions in BRCA1.
乳腺癌1号基因（BRCA1）——一种肿瘤抑制基因，在DNA修复机制中发挥着重要作用。BRCA1的几种变体扰乱了其结构和功能，包括同义及非同义单核苷酸多态性（SNP）。在本研究中，我们对BRCA1基因的非同义SNP（nsSNP）进行了计算机模拟分析。总共从NCBI SNP数据库中检索到122个nsSNP，并使用计算预测工具进行了计算机模拟分析：SIFT、PROVEAN、Mutation Taster、PolyPhen-2、MutPred和ConSurf。在这些工具中，基于结构同源性分析，SIFT、PROVEAN和Mutation Taster预测122个nsSNP中的61个为“有害”。PolyPhen-2将22个nsSNP分类为“可能有害”。通过MutPred对这些nsSNP进行进一步分析，以预测氨基酸改变的基本分子机制。ConSurf分析预测了11个具有结构和功能后果的保守氨基酸残基。我们在环指结构域中鉴定出5个氨基酸残基（L22、C39、H41、C44和C47），在BRCT结构域中鉴定出2个氨基酸残基（P1771和I1707），它们有可能阻碍BRCA1蛋白的功能。本研究为BRCA1中nsSNP和氨基酸取代的影响提供了见解。
