Lubrano-Berthelier Cecile, Durand Emmanuelle, Dubern Beatrice, Shapiro Astrid, Dazin Paul, Weill Jacques, Ferron Camille, Froguel Philippe, Vaisse Christian
Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA.
Hum Mol Genet. 2003 Jan 15;12(2):145-53. doi: 10.1093/hmg/ddg016.
Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.
蛇形黑皮质素4受体编码区的杂合突变是迄今为止所描述的人类肥胖最常见的遗传原因。关于此类突变在肥胖症中的总体患病率，目前仍存在相互矛盾的数据，而且关于大多数与肥胖相关的黑皮质素4受体（MC4R）突变所导致的功能缺陷，可用信息有限。我们在此报告对一组新的172例患有严重儿童肥胖症且有肥胖家族史的患者的MC4R编码区突变进行的筛查。在该队列的3例患者（1.74%）中发现了3种MC4R杂合突变（Ser127Leu、Ala244Glu和Pro299His），证实此类突变与大量儿童肥胖病例有关。除了其他11种与儿童肥胖相关的MC4R突变外，对这些突变受体的功能分析表明，它们均改变了内源性激动剂α-促黑素细胞激素（α-MSH）对受体的激活作用。为了进一步研究与儿童肥胖相关的MC4R突变所导致的功能缺陷，我们开发了一种新颖、灵敏的技术，用于定量分析突变对MC4R细胞表面表达的影响。利用该方法，我们分析了所有14种已描述的与儿童肥胖相关的MC4R错义突变的细胞表面表达情况。我们证明，81.3%与儿童肥胖相关的MC4R杂合突变会导致受体在细胞内滞留。这一结果对于与儿童肥胖相关的MC4R突变的潜在药物挽救以及对患有这种疾病的患者的治疗具有重要意义。
