Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans

Abstract

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.

Human obesity as a heritable disorder of the central control of energy balance

“…In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the downstream pathways of leptin signaling within the brain. 32 These include mutations in the leptin receptor; 33,34 the POMC gene, [35][36][37] which is expressed in hypothalamic cells, which are activated by leptin; in the melanocortin 4 receptor, which is activated by the products of the POMC gene; 38,39 and, much more rarely, defects in signaling systems that are thought to be downstream of the melanocortin 4 receptor, including the brainderived neurotrophic factor 40 and TrkB systems. 41 Most of these defects are rare but molecular defects in the melanocortin 4 receptor are relatively common.…”

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…Since the normal range for plasma T4 is wide, this does not exclude abnormalities in the HPT axis of these individuals, particularly under circumstances such as fasting which may functionally challenge the HPT axis. Humans deficient in POMC are hyperphagic and obese, with red hair [36]. In the original study describing these individuals, it was assumed that their HPT axis was normal due to normal plasma T4 [36].…”

“…Humans deficient in POMC are hyperphagic and obese, with red hair [36]. In the original study describing these individuals, it was assumed that their HPT axis was normal due to normal plasma T4 [36]. However, a recent, more detailed analysis of these subjects shows that in fact POMC-deficient humans have normal plasma T3 and T4 levels, with elevated plasma TSH which can be suppressed to within the normal range with T4…”

Body weight is regulated by the brain: a link between feeding and emotion

“…89 Another important piece of data supporting this model is that POMC-deficient mice and humans display similar obesity phenotypes. 90,91 A unique component of the melanocortin regulatory system is an endogenous MC4-R antagonist, agouti-related protein (AgRP). [92][93][94] Interestingly, AgRP is produced exclusively in the Arc in rodents, monkeys, and humans.…”