Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity
Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity
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DOI：
10.1155/2019/1832084
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发表时间：
2019-12-04
影响因子：
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通讯作者：
Barakat, Abdelhamid
中科院分区：
文献类型：
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作者：
Bouafi, Hind;Bencheikh, Sara;Barakat, Abdelhamid
瘦素是一种肽激素，通过控制饱腹感来调节体内脂肪储存和食欲。这种激素由白色脂肪组织分泌，在脂肪酸的储存和动员中起作用。在不同人群中，LEP基因突变与肥胖有关；它是一种多因素疾病，构成了一个重大的公共卫生问题。在这项研究中，我们使用8种计算预测工具评估了从dbSNP中提取的LEP基因中错义snp的影响。在4337个snp中，有93个为非同义单核苷酸多态性（nssnp）。在93个非单核苷酸多态性中，预测软件预测12个变异（S46L、G59S、D61N、D100N、N103K、C117S、D76V、S88C、P90R、I95N、L161R和R105W）危害最大。在这12个有害snp中，8个变异（S46L、G59S、D61N、D100N、N103K、C117S、L161R和R105W）位于保守位置，结构稳定性下降，通过I-Mutant和Mupro进行了评价。然后，通过分析野生蛋白和突变蛋白中不同氨基酸之间的不同相互作用，我们使用YASARA软件评估了有害修饰对结构的影响。在8个有害的非单核苷酸多态性中，我们发现了6个变异S46L、G59S、D100N、L103K、R105W、L161R的结构变化，其中两个变异R105W、N103K之前被报道与肥胖相关。我们的研究表明，6种有害突变可能在导致人类肥胖方面发挥重要作用，值得纳入关联和功能研究，然后可能成为药物靶点。
Leptin is a peptide hormone that regulates fat stores in the body and appetite by controlling the feeling of satiety. This hormone is secreted by the white adipose tissue and plays a role in the storage and mobilization of fatty acids. Mutations of the LEP gene have been associated with obesity in different populations; it is a multifactorial disease that constitutes a major public health problem. In this study, we evaluated the impact of missense SNPs in the LEP gene extracted from dbSNP using 8 computational prediction tools. Out of the total of 4337 SNPs, 93 were nsSNPs (nonsynonymous single nucleotide polymorphisms). Among 93 nsSNPs, 12 (S46L, G59S, D61N, D100N, N103K, C117S, D76V, S88C, P90R, I95N, L161R, and R105W) variants were predicted to be the most deleterious by prediction software. On these 12 deleterious SNPs, 8 variants (S46L, G59S, D61N, D100N, N103K, C117S, L161R, and R105W) were located in the conserved positions and showed a decrease in structure stability which was evaluated by I-Mutant and Mupro. Then, by analyzing the different interactions between different amino acids in wild and mutated proteins, we assessed the structural impact of the deleterious modifications using the YASARA software. Among 8 deleterious nsSNPs, we revealed structure changes in the 6 variants S46L, G59S, D100N, L103K, R105W, L161R, two of which R105W, N103K were previously reported as associated with obesity. Our study suggests 6 deleterious mutations could play an important role in contributing to human obesity and worth to be included in association and functional studies, then may be a drug target.