Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans
Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans
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DOI：
10.1038/509
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发表时间：
1998-06-01
期刊：
影响因子：
30.8
通讯作者：
Grüters, A
中科院分区：
文献类型：
--
作者：
Krude, H;Biebermann, H;Grüters, A
前体蛋白前阿黑皮素原（POMC）的顺序切割产生黑皮质素肽促肾上腺皮质激素（ACTH）、黑素细胞刺激激素（MSH）α、β和γ以及阿片类受体配体β-内啡肽（1）虽然已经报道了一些孤立的促肾上腺皮质激素缺乏症病例（OMIM 201400），但迄今为止尚未描述遗传性POMC缺陷（2）。最近在动物模型中的研究阐明了α-MSH在通过激活脑黑皮质素-4-受体（MC 4-R;参考文献3-5）调节食物摄入中的中心作用，以及人类肥胖与靠近POMC基因座的2号染色体的联系（6），导致提出POMC与人类肥胖的关联（7）。α-MSH在调节食物摄入和影响毛发色素沉着中的双重作用预测与POMC功能缺陷相关的表型将包括肥胖、色素沉着改变和ACTH缺乏。在两个先证者中观察到这些症状促使我们在他们的POMC基因中寻找突变。发现患者1是外显子3中两个突变（G7013 T）的复合杂合子。C7133 Delta），其干扰ACTH和α-MSH的适当合成。患者2是外显子2（C3804 A）中的突变的纯合子，其消除POMC翻译。这些发现代表了POMC基因内遗传缺陷的第一个例子，并定义了一种新的单基因内分泌疾病，导致早发性肥胖，肾上腺功能不全和红头发色素沉着。
Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin(1) While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far(2). Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus(6), led to the proposal of an association of POMC with human obesity(7). The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T. C7133 Delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.