Molecular genetics of human obesity-associated MC4R mutations
Molecular genetics of human obesity-associated MC4R mutations
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DOI：
10.1111/j.1749-6632.2003.tb03161.x
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Vaisse, C
中科院分区：
文献类型：
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作者：
Lubrano-Berthelier, C;Cavazos, M;Vaisse, C
黑素皮质素4受体(MC4R)的杂合编码突变与1%至6%的早发或严重成人肥胖病例有关。为了更好地解决这种特殊形式的肥胖中的基因-表型关系问题，我们系统地研究了50个不同的与肥胖相关的MC4R突变的功能特征。MC4R的结构建模表明，与肥胖相关的MC4R突变并不局限于蛋白质的单个结构域。我们开发了一种基于流式细胞术的分析方法来比较肥胖相关MC4R突变体的细胞膜表达。利用这一实验，我们证明了超过54%的肥胖相关的MC4R突变会损害MC4R的膜表达。所有其他突变都会损害生理激动剂α-MSH的基本构成活性和/或通过cAMP依赖的荧光素酶测定的EC50。受体活性的变化范围从对α-MSH反应的MC4R激活的完全抑制到受体的基本构成活性的轻微变化。由于大多数患者都是MC4R突变的杂合子，这些数据表明总体MC4R活性的轻微下降会导致肥胖，这有力地支持了MC4R是人类脂肪的关键组成部分的假设。
Heterozygous coding mutations in the melanocortin 4 receptor (MC4R) are implicated in 1 to 6% of early onset or severe adult obesity cases. To better address the problem of the genotype:phenotype relationship within this specific form of obesity, we systematically studied the functional characteristics of 50 different obesity-associated MC4R mutations. Structure modeling of MC4R indicates that obesity-associated MC4R mutations are not localized in a single domain of the protein. We developed a flow cytometry-based assay to compare cell membrane expression of obesity-associated MC4R mutants. Using this assay, we demonstrate that over 54% of the obesity-associated MC4R mutations impair the membrane expression of MC4R. All other mutations impair the basal constitutive activity and/or the EC50 for the physiological agonist alpha-MSH as measured in a cAMP- dependent luciferase assay. The extent of the alterations in receptor activity ranges from a total suppression of MC4R activation in response to alpha-MSH to a mild alteration of the basal constitutive activity of the receptor. Since most patients are heterozygous for MC4R mutations, these data indicate that a small decrease in overall MC4R activity can cause obesity, strongly supporting the hypothesis that the MC4R is a critical component of the adipostat in humans.