Department of Undergraduate Health Professions, College of Allied Health Sciences, Augusta University, Augusta, GA, USA.
Department of Nutrition & Dietetics, College of Allied Health Science, Augusta University, Augusta, GA, USA.
Sci Prog. 2024 Oct-Dec;107(4):368504241297197. doi: 10.1177/00368504241297197.
The most recent version of ClinVar was utilized to filter variants of the MC4R gene based on location, condition, and clinical significance with the goal of obtaining benign and disease-associated variants of the MC4R gene. MC4R gene variants can lead to dysregulation of energy expenditure and appetite control, which prompted this study to delineate the distinctive features of MC4R gene variants submitted to the ClinVar repository regarding their association with obesity and related phenotypes.
A thorough search was conducted in the ClinVar repository for clinically significant MC4R variants through the utilization of the gene name MC4R[gene] and MeSH terms "MC4R[gene]" and "single gene"[properties]" in the search box. Leading to the identification of clinically significant genetic variants associated with obesity.
Utilizing the ClinVar clinical significance ranking system, the MC4R variants were categorized into six groups based on ClinVar/ClinGen's ranking system: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), benign (B), likely benign (LB), and conflicting classifications (CC). A total of 103 pathogenic variants were observed. These variants have different clinical significance that are associated with monogenic obesity, monogenic diabetes, and body mass index quantitative traits. It was observed that over 80% of the mutations were single nucleotide variants, with nearly half being missense mutations spread throughout the topological and transmembrane domains. Furthermore, TM7 had the highest number of single nucleotide missense mutations.
Further analysis of the relationships between monogenic obesity and diabetes requires additional investigation to discover the underlying causes of these conditions. The study findings imply that mutations in MC4R's topological and transmembrane regions may significantly influence receptor activation and signaling. As more MC4R variants are discovered and their correlation with obesity is established, there is potential to definitively establish a strong connection between MC4R pathogenic variants and the development of obesity.
利用最新版 ClinVar 数据库，根据位置、疾病和临床意义对 MC4R 基因变异进行筛选，旨在获取 MC4R 基因的良性和疾病相关变异。MC4R 基因变异可导致能量消耗和食欲控制失调，这促使本研究阐明 ClinVar 数据库中提交的与肥胖及其相关表型相关的 MC4R 基因变异的独特特征。
在 ClinVar 数据库中，通过使用基因名称 MC4R[gene]和搜索框中的 MeSH 术语“MC4R[gene]”和“单基因”[属性]，对具有临床意义的 MC4R 变异进行了全面搜索，从而确定与肥胖相关的具有临床意义的遗传变异。
利用 ClinVar 临床意义评分系统，根据 ClinVar/ClinGen 的评分系统，将 MC4R 变异分为六组：致病性（P）、可能致病性（LP）、意义不明变异（VUS）、良性（B）、可能良性（LB）和相互矛盾的分类（CC）。共发现 103 个致病性变异。这些变异具有不同的临床意义，与单基因肥胖、单基因糖尿病和体重指数定量特征相关。观察到超过 80%的突变是单核苷酸变异，近一半是错义突变，分布在拓扑和跨膜结构域。此外，TM7 有最多的单核苷酸错义突变。
需要进一步分析单基因肥胖和糖尿病之间的关系，以发现这些疾病的根本原因。研究结果表明，MC4R 的拓扑和跨膜区域的突变可能显著影响受体激活和信号转导。随着更多 MC4R 变异的发现及其与肥胖的相关性得到确立，有可能明确建立 MC4R 致病性变异与肥胖发展之间的强关联。
