人类黑素皮质素受体辅助蛋白 2 基因的罕见变异导致黑素皮质素-4 受体功能降低。

Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene.

机构信息

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Institute of Experimental Pediatric Endocrinology, Charité, Berlin, Germany.

出版信息

Obesity (Silver Spring). 2016 Sep;24(9):1976-82. doi: 10.1002/oby.21576. Epub 2016 Jul 30.

DOI:10.1002/oby.21576

PMID:27474872

Abstract

OBJECTIVE

The melanocortin receptor accessory protein 2 (MRAP2) is relevant for weight regulation in mice and humans. This function is likely mediated by regulation of the melanocortin-4 receptor (MC4R). Functional implications of human MRAP2 mutations have not been described yet.

METHODS

A mutation screen was conducted in MRAP2 in 184 children and adolescents with (extreme) obesity and in 184 lean controls. Detected nonsynonymous variants were genotyped in larger independent study groups (300 people with obesity and 436 individuals with normal weight). The influence of mutant MRAP2 on MC4R signaling was analyzed in vitro.

RESULTS

(1) Three (two novel) nonsynonymous MRAP2 variants were detected: p.Ala137Thr, p.Gln174Arg, p.Arg125His (rs115655382), two synonymous variants, and three intronic variants. (2) The impact of MRAP2 on MC4R function was dependent on the ratio between the two co-expressed proteins. Increased MC4R signaling was detected at MRAP2/MC4R ratios of 2 + 1 and above. (3) The function of MC4R was reduced with the infrequent allele at the MRAP2 p.Gln174Arg variant. (4) The three nonsynonymous mutations were each only detected once among the 484 people with obesity and not among 620 individuals with normal weight.

CONCLUSIONS

This was the first study describing an effect of a MRAP2 mutation on MC4R function.

摘要

目的

黑皮质素受体辅助蛋白 2（MRAP2）在小鼠和人类的体重调节中具有重要作用。这种功能可能是通过调节黑皮质素-4 受体（MC4R）来介导的。尚未描述人类 MRAP2 突变的功能意义。

方法

在 184 名肥胖（极度肥胖）儿童和青少年以及 184 名瘦对照者中对 MRAP2 进行了突变筛选。在更大的独立研究组（300 名肥胖者和 436 名体重正常者）中对检测到的非同义变异进行了基因分型。在体外分析了突变型 MRAP2 对 MC4R 信号的影响。

结果

（1）共检测到三种（两种新的）非同义 MRAP2 变体：p.Ala137Thr、p.Gln174Arg、p.Arg125His（rs115655382）、两种同义变体和三种内含子变体。（2）MRAP2 对 MC4R 功能的影响取决于两种共表达蛋白的比值。在 MRAP2/MC4R 比值为 2+1 及以上时，检测到 MC4R 信号增强。（3）MRAP2 p.Gln174Arg 变异的低频等位基因降低了 MC4R 的功能。（4）这三种非同义突变在 484 名肥胖者中每一种都只检测到一次，而在 620 名体重正常者中未检测到。