Deciphering deleterious missense variants in the MC4R gene in the pathogenesis of obesity

IF 1.8 4区医学 Q4 ENDOCRINOLOGY & METABOLISM Endocrinologia Diabetes Y Nutricion Pub Date : 2025-04-01 Epub Date: 2025-04-10 DOI:10.1016/j.endien.2025.501559

Meriem El Fessikh , Hanaa Skhoun , Zohra Ouzzif , Jamila El Baghdadi

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Abstract

The MC4R gene plays a critical role in regulating food intake, making it an important model for studying genetic mutations that impact the protein function. This study aimed to identify the most deleterious functional and structural variants in individuals with obesity by analyzing SNPs from the NCBI dbSNP database and selecting pathogenic variants from ClinVar. Bioinformatics tools were employed to predict deleterious SNPs, and conservation analysis was performed using ConSurf. Stability predictions were made with MUpro, I-Mutant2.0, and iStable. The 3D structure of the MC4R protein was examined using YASARA view. A total of 20 out of 348 missense mutations were associated with obesity. Fifteen of these variants were predicted to be the most deleterious. Eight variants located in conserved regions were found to significantly reduce protein stability and cause structural changes (S58C, E61K, N62S, I69R, D90N, R165Q, P299H, and I316S), indicating their potential as obesity biomarkers and therapeutic targets.

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在肥胖的发病机制中破译MC4R基因中的有害错义变异

MC4R基因在调节食物摄入中起着至关重要的作用，使其成为研究影响蛋白质功能的基因突变的重要模型。本研究旨在通过分析NCBI dbSNP数据库中的snp和从ClinVar中选择致病变异，确定肥胖个体中最有害的功能和结构变异。利用生物信息学工具预测有害snp，并使用ConSurf进行保守性分析。使用MUpro、I-Mutant2.0和iStable进行稳定性预测。使用YASARA视图检测MC4R蛋白的三维结构。348个错义突变中有20个与肥胖有关。据预测，其中15种变异是最有害的。发现8个位于保守区域的变异（S58C、E61K、N62S、I69R、D90N、R165Q、P299H和I316S）显著降低了蛋白质稳定性并导致结构变化，表明它们有潜力成为肥胖生物标志物和治疗靶点。

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来源期刊

Endocrinologia Diabetes Y Nutricion Multiple-

CiteScore

2.10

自引率

10.50%

发文量

期刊介绍： Endocrinología, Diabetes y Nutrición is the official journal of the Spanish Society of Endocrinology and Nutrition (Sociedad Española de Endocrinología y Nutrición, SEEN) and the Spanish Society of Diabetes (Sociedad Española de Diabetes, SED), and was founded in 1954. The aim of the journal is to improve knowledge and be a useful tool in practice for clinical and laboratory specialists, trainee physicians, researchers, and nurses interested in endocrinology, diabetes, nutrition and related disciplines. It is an international journal published in Spanish (print and online) and English (online), covering different fields of endocrinology and metabolism, including diabetes, obesity, and nutrition disorders, as well as the most relevant research produced mainly in Spanish language territories. The quality of the contents is ensured by a prestigious national and international board, and by a selected panel of specialists involved in a rigorous peer review. The result is that only manuscripts containing high quality research and with utmost interest for clinicians and professionals related in the field are published. The Journal publishes Original clinical and research articles, Reviews, Special articles, Clinical Guidelines, Position Statements from both societies and Letters to the editor. Endocrinología, Diabetes y Nutrición can be found at Science Citation Index Expanded, Medline/PubMed and SCOPUS.