Mutational Analysis of the Pro-opiomelanocortin Gene in French Obese Children Led to the Identification of a Novel Deleterious Heterozygous Mutation Located in the α-Melanocyte Stimulating Hormone Domain

Abstract

ABSTRACT:The pro-opiomelanocotin (POMC) plays a key role in body weight regulation, where its derived peptides mediate leptin action via the hypothalamic melanocortin 4 receptor (MC4R). The pathogenic effects of POMC mutations have been challenged in obesity. Our aim was to assess the relevance of POMC mutations in a cohort of French obese and nonobese children. Direct sequencing of the POMC gene was performed in 322 obese and 363 control unrelated children. Functional studies for the novel Phe144Leu mutation included the response to ␣-melanocyte stimulating hormone (␣MSH) and a competitive binding assay. POMC mutations were identified in 3.72% of obese [95% confidence interval (CI): 1.66 -5.80] and 2.20% of control (95% CI: 0.69 -3.71) subjects. The novel mutation located in the ␣MSH region of the POMC gene (Phe144Leu) was found in one obese child and was transmitted by the obese father. Functional studies showed that MC4R activation in response to Leu144␣MSH was almost completely abolished due to a dramatically altered binding of Leu144␣MSH to MC4R. The frequency of POMC mutations is not significantly different between obese and control children in our cohort. The novel heterozygous mutation Phe144Leu leading to the absence of melanocortin signaling was associated with early-onset obesity suggesting its pathogenic role. T he proopiomelanocortin (POMC) is a complex propeptide encoding a number of melanocortin peptides that are released by tissue-specific proteolytic processing. These peptides have important roles in a range of functions such as skin pigmentation, control of adrenal function, and body weight regulation via the leptin/melanocortin pathway (1). The production of POMC in the central nervous system is stimulated by leptin and its posttranslational process leads to the generation of different peptides (2). The nature of POMC-derived peptides depends on the type of endoproteolytic enzymes present in specific brain areas. In the anterior pituitary, the presence of the proconvertase (PC) 1 enzyme allows the production of adrenocorticotropic hormone (ACTH) and ␤-lipotropin peptides, while the simultaneous presence of PC1 and PC2 in the hypothalamus determines the production of ␣-, ␤-, ␥-melanocyte-stimulating hormone (␣-, ␤-, ␥MSH) and ␤-endorphins. POMC knockout mice become obese due to the loss of the anorexigenic action of ␣MSH on melanocortin-4 receptor (MC4R) expressing neurons. They have no adrenal function because of the lack of ACTH production and present variable alterations in coat pigmentation due to the absence of ␣MSH in the skin (3). The phenotype of POMC-deficient mice resembles that of patients with rare mutations that completely prevent POMC-derived peptide production. To date, six families with children carrying homozygous or compound heterozygous loss-of-function mutations in POMC have been described. The children in these families display a hypocortisolism, early-onset obesity, and variable alterations of skin and hair pigmentation, thereby defining a new rare syndrome of obesity asso...

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