Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A
Department of Pediatrics, Charité, Campus Virchow, Humboldt-University Berlin, Germany.
Nat Genet. 1998 Jun;19(2):155-7. doi: 10.1038/509.
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. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. 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, led to the proposal of an association of POMC with human obesity. 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, C7133delta) 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.
前体蛋白前阿黑皮素原（POMC）的顺序裂解产生黑素皮质素肽促肾上腺皮质激素（ACTH）、α、β和γ黑素细胞刺激激素（MSH）以及阿片受体配体β-内啡肽。虽然已经报道了一些孤立性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。最近在动物模型中的研究阐明了α-MSH通过激活脑黑素皮质素-4-受体（MC4-R；参考文献3-5）在食物摄入调节中的核心作用，以及人类肥胖与靠近POMC基因座的2号染色体的联系，从而提出了POMC与人类肥胖相关的观点。α-MSH在调节食物摄入和影响毛发色素沉着方面的双重作用预示着与POMC功能缺陷相关的表型将包括肥胖、色素沉着改变和促肾上腺皮质激素缺乏。在两名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（G7013T、C7133delta）的复合杂合子，这两个突变干扰了促肾上腺皮质激素和α-MSH的正常合成。患者2是外显子2中一个突变（C3804A）的纯合子，该突变使POMC翻译终止。这些发现代表了POMC基因内遗传缺陷的首个实例，并定义了一种导致早发性肥胖、肾上腺功能不全和红发色素沉着的新的单基因内分泌疾病。
