Department of Genomic Science, School of Biological Sciences, Central University of Kerala, Tejaswini Hills, Periya (P.O), Kasaragod 671 320, India.
J Genet. 2021;100.
The human aromatase protein encoded by gene is the principle enzyme involved in the biogenesis of oestrogen in adipose tissues. An excessive exposure to endogenous oestrogen is regarded as an important determinant in the risk of breast cancer. Thus, in the present study we have used multiple computational methods to identify the most deleterious nonsynonymous SNPs in gene that caused probable genotypic-phenotypic alterations susceptible to breast cancer malignancy. In this study, a total of 338 nsSNPs were screened using 12 tools including SIFT, PROVEAN, PolyPhene-2, SNAP2, I Mutant 3.0, MuPro, mCSM, PhD SNP, SNP&GO, P-Mut, Dr Cancer, and, CScape. Additionally the structural and functional consequences of missense mutations were validated using Consurf, ModPred, SOPMA, and, HOPE server tools. Of the 338 nsSNPs subjected to functional, protein stability, disease associated, and, cancer susceptible analysis, 14 variants were predicted to be highly deleterious mutants. Further, structural and molecular studies suggested 10 variants (R435H, Y77C, Y81C, E302K, E210K; and L451P, G49D, G131D, L204W and D309) to have various deformities and caused structural disturbances of the protein. Through the combination of multiple computational tools and strategized analysis, we report seven novel high risk nsSNPs of human aromatase enzyme in association with the pathogenesis of human breast cancer.
基因编码的人类芳香酶蛋白是脂肪组织中雌激素生物合成的主要酶。内源性雌激素的过度暴露被认为是乳腺癌风险的一个重要决定因素。因此，在本研究中，我们使用了多种计算方法来识别基因中最具破坏性的非同义 SNP，这些 SNP 可能导致乳腺癌恶性的基因型-表型改变。在这项研究中，使用包括 SIFT、PROVEAN、PolyPhene-2、SNAP2、I Mutant 3.0、MuPro、mCSM、PhD SNP、SNP&GO、P-Mut、Dr Cancer 和 CScape 在内的 12 种工具筛选了总共 338 个 nsSNP。此外，还使用 Consurf、ModPred、SOPMA 和 HOPE 服务器工具验证了错义突变的结构和功能后果。在对 338 个 nsSNP 进行功能、蛋白质稳定性、疾病相关和癌症易感性分析后，有 14 个变体被预测为高度有害突变体。此外，结构和分子研究表明，有 10 个变体（R435H、Y77C、Y81C、E302K、E210K；以及 L451P、G49D、G131D、L204W 和 D309）具有各种畸形，并导致蛋白质结构的紊乱。通过多种计算工具的组合和策略性分析，我们报告了与人类乳腺癌发病机制相关的人类芳香酶酶中七个新的高危 nsSNP。
