Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity
Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity
复制标题
DOI：
10.1210/jc.2004-0497
复制
发表时间：
2005-01-01
影响因子：
5.8
通讯作者：
Pedersen, O
中科院分区：
文献类型：
--
作者：
Larsen, LH;Echwald, SM;Pedersen, O
编码黑皮质素4受体（MC 4 R）的基因突变与最常见的单基因型肥胖有关。我们检测了750名丹麦青少年肥胖男性（体重指数33.3 +/- 2.4 kg/m2）和706名对照受试者（体重指数21.4 +/- 2.1 kg/m2）的MC 4 R突变。总共发现了14种不同的突变，其中Ala 219 Val和Leu 325 Phe两种是新型变体。变体受体Leu 325 Phe不能结合[Nle 4，D-Phe 7]alphaMSH，而Ala 219 Val变体与野生型受体相比显示出显著受损的cAMP的美拉诺坦II诱导。其余11个突变先前已被报道，但在本研究中，选定的MC 4 R变体在体外进一步表征。先前发现的无义突变Tyr 35 stop具有相对较高的等位基因频率（0.6%），表明丹麦人群中可能存在奠基者效应。这项研究显示，在一项基于人群的肥胖男性研究中，MC 4 R基因致病突变的携带者频率为2.5%。因此，该基因的变异是斯堪的纳维亚男性肥胖症最常见的已知特定遗传原因。
Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity ( body mass index 33.3 +/- 2.4 kg/m(2)) and 706 control subjects ( body mass index 21.4 +/- 2.1 kg/m(2)) for mutations in MC4R. A total of 14 different mutations were identified of which two, Ala219Val and Leu325Phe, were novel variants. The variant receptor, Leu325Phe, was unable to bind [Nle4, D-Phe7]alphaMSH, whereas the Ala219Val variant showed a significantly impaired melanotan II induction of cAMP, compared with the wild-type receptor. The remaining 11 mutations have previously been reported, but selected MC4R variants were further characterized in vitro in the present study. A previously identified nonsense mutation, Tyr35stop, had a relatively high allele frequency (0.6%), suggesting a possible founder effect in the Danish population. This study shows a carrier frequency of 2.5% of pathogenic mutations in the MC4R gene in a population-based study of obese men. Thus, variation in this gene is the most common known specific genetic cause of obesity among Scandinavian men.