Abstract：
Polymorphisms of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) are linked to pathophysiological changes in lung inflammation, cancer, Alzheimer\'s disease (AD), encephalopathy, liver fibrosis, and cardiovascular diseases. In this study, we predicted the pathogenicity of ADAM10 non-synonymous single nucleotide polymorphisms (nsSNPs) in a wide array of mutation analyzing bioinformatics tools. We retrieved 423 nsSNPs from dbSNP-NCBI for the analysis, and 13 were predicted deleterious by each of the ten tools: SIFT, PROVEAN, CONDEL, PANTHER-PSEP, SNAP2, SuSPect, PolyPhen-2, Meta-SNP, Mutation Assessor and Predict-SNP. Further assessment of amino acid sequences, homology models, conservation profiles, and inter-atomic interactions identified C222G, G361E and C639Y as the most pathogenic mutations. We validated this prediction through structural stability analysis using DUET, I-Mutant Suite, SNPeffect and Dynamut. Molecular dynamics simulations and principal component analysis also indicated considerable instability of the C222G, G361E and C639Y variants. Therefore, these ADAM10 nsSNPs could be candidates for diagnostic genetic screening and therapeutic molecular targeting.Communicated by Ramaswamy H. Sarma.
摘要：
解整合素和含金属蛋白酶结构域的蛋白10（ADAM10）的多态性与肺部炎症的病理生理变化有关，癌症,阿尔茨海默病（AD），脑病,肝纤维化,和心血管疾病。在这项研究中,我们在广泛的突变分析生物信息学工具中预测了ADAM10非同义单核苷酸多态性(nsSNPs)的致病性。我们从dbSNP-NCBI中检索了423个nsSNP用于分析，十种工具中的每一种都预测了13种是有害的：SIFT，PROVEAN,CONDEL,PANTHER-PSEP,SNAP2,SuSPect,PolyPhen-2，Meta-SNP，突变评估员和预测-SNP。进一步评估氨基酸序列，同源模型，保护概况，和原子间相互作用确定C222G，G361E和C639Y为最具致病性的变异。我们通过使用DUET的结构稳定性分析验证了这一预测，I-Mutant套房,SNPeffect和Dynamut。分子动力学模拟和主成分分析也表明C222G相当不稳定，G361E和C639Y变体。因此,这些ADAM10nsSNPs可能是诊断性遗传筛查和治疗性分子靶向的候选基因.由RamaswamyH.Sarma沟通。
