Leptin is a versatile hormone with a variety of functions, including regulation of food intake by inhibiting hunger. Any deleterious mutation in this protein can lead to serious consequences for the body. This study was conducted to identify the most deleterious non-synonymous single-nucleotide polymorphisms (nsSNPs) of human LEP gene and their impact on its encoded protein. To predict the possible impact of nsSNPs on leptin, a total of 90 nsSNPs were retrieved from dbSNP and investigated using many in silico tools which specially designed to analyze nsSNPs’ consequences on the protein structure, function, and stability. Three nsSNPs, namely D76V, L161R, and C117S, were found to be completely deleterious by all utilized nsSNPs prediction tools, thus affecting leptin protein structure, biological activity, and stability. Evolutionary information indicated L161R and C117S mutations to be located in extremely high conserved positions. Furthermore, several deleterious mechanisms controlled by both L161R and C117S mutations which alter several motifs in the secondary structure of leptin were detected. However, all D76V, L161R, and C117S mutations exhibited alteration in polar interactions in their representative positions. Further in-depth analyses proved several harmful structural effects of the three nsSNPs on leptin, which may lead to multiple intrinsic disorders in the altered protein forms. This study provides the first comprehensive computation of the effect of the most damaging nsSNPs on leptin. The exploration of these missense mutations may present novel perspectives for various deleterious consequences originated from such amino acids substitutions. The dynamics of leptin performance, therefore, in many biological pathways, may be changed to create a variety of disorders, such as obesity and diabetes. These findings will help in detecting the most harmful variations needed to be screened for clinically diagnosed patients with leptin disorders. ISRCTN73824458

中文翻译：

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D76V、L161R 和 C117S 是致病性最强的氨基酸取代，对瘦素的结构、功能和稳定性有几个危险的后果

瘦素是一种多功能激素，具有多种功能，包括通过抑制饥饿来调节食物摄入量。这种蛋白质的任何有害突变都会对身体造成严重后果。本研究旨在鉴定人类 LEP 基因最有害的非同义单核苷酸多态性 (nsSNP) 及其对其编码蛋白质的影响。为了预测 nsSNP 对瘦素的可能影响，从 dbSNP 中检索了总共 90 个 nsSNP，并使用许多专门设计用于分析 nsSNP 对蛋白质结构、功能和稳定性影响的计算机工具进行了研究。三个 nsSNP，即 D76V、L161R 和 C117S，被所有使用的 nsSNP 预测工具发现是完全有害的，从而影响瘦素蛋白结构、生物活性和稳定性。进化信息表明 L161R 和 C117S 突变位于极高的保守位置。此外，检测到由 L161R 和 C117S 突变控制的几种有害机制，这些突变改变了瘦素二级结构中的几个基序。然而，所有 D76V、L161R 和 C117S 突变在其代表性位置都表现出极性相互作用的改变。进一步的深入分析证明了三个 nsSNP 对瘦素的几种有害结构影响，这可能导致蛋白质形式改变的多种内在疾病。这项研究首次全面计算了最具破坏性的 nsSNP 对瘦素的影响。对这些错义突变的探索可能为源自此类氨基酸取代的各种有害后果提供新的视角。因此，在许多生物途径中，瘦素表现的动态可能会发生变化，从而导致多种疾病，例如肥胖症和糖尿病。这些发现将有助于检测临床诊断出的瘦素疾病患者需要筛查的最有害的变异。ISRCTN73824458