A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism
A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism
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DOI：
10.1093/hmg/11.17.1997
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发表时间：
2002-08-15
影响因子：
3.5
通讯作者：
O'Rahilly, S
中科院分区：
文献类型：
--
作者：
Challis, BG;Pritchard, LE;O'Rahilly, S
人类阿片黑皮质素原 (POMC) 基因的两个等位基因的功能丧失会导致一种非常罕见的肾上腺功能减退症、红发和早发性肥胖综合征。为了检查 POMC 中更微妙的基因变异是否可能导致早发性肥胖，我们对 262 名自童年起就有严重肥胖史的白人受试者的基因编码区进行了测序。两个孩子被发现存在错义突变 R236G 杂合，该突变破坏了 β 黑素细胞刺激激素 (β-MSH) 和 β-内啡肽之间的二碱基裂解位点。用突变型POMC cDNA转染的β-TC3细胞产生了突变型β-MSH/β-内啡肽融合蛋白。这种融合蛋白以与其天然配体相似的亲和力与人黑皮质素-4受体（hMC4R）结合，但激活受体的能力明显降低。这一变异与早发性肥胖在一个家庭的三代人中共同分离，并且在 412 名正常体重的英国白种人对照中不存在。将英国白种人的结果与法国受试者的一项新病例对照研究以及之前发表的三份报告相结合，破坏该加工位点的突变存在于 0.88% 的早发性肥胖受试者和 0.22% 的正常体重对照中。这些结果表明，R236G 突变可能通过产生能够干扰中枢黑皮质素信号传导的异常融合蛋白而赋予肥胖遗传易感性。
The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between beta melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case-control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.