Sequential cleavage of the precursor protein pre–pro–opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte–stimulating hormones (MSH) α, β, and γ as well as the opioid–receptor ligand β–endorphin1. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far2. Recent studies in animal models elucidated a central role of α–MSH in the regulation of food intake by activation of the brain melanocortin–4–receptor (MC4–R; refs 3, 4, 5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus6, led to the proposal of an association of POMC with human obesity7.The dual role of α–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, C7133Δ) which interfere with appropriate synthesis of ACTH and α-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.
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The authors thank S. Schwarz for helpful discussions and K. Huhne for excellent technical assistance. This study was supported by a grant from the Deutsche Forschungsgemeinschaft to H.K. (Kr1710-1/1) and the Sonnenfeld-Stiftung to H.B.
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Krude, H., Biebermann, H., Luck, W. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19, 155–157 (1998). https://doi.org/10.1038/509
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