SEVERE EARLY-ONSET OBESITY, ADRENAL INSUFFICIENCY AND RED HAIR PIGMENTATION CAUSED BY POMC MUTATIONS IN HUMANS

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 i solated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far(2). Recent studies in anima l models elucidated a central role of alpha-MSH in the regulation of f ood 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 pr oximity 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 phenot ype associated with a defect in POMC function would include obesity, a lteration in pigmentation and ACTH deficiency. The observation of thes e symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote fo r two mutations in exon 3 (G7013T. C7133 Delta) which interfere with a ppropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous f or a mutation in exon 2 (C3804A) which abolishes POMC translation. The se findings represent the first examples of a genetic defect within th e POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.