Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain.

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 alpha-melanocyte stimulating hormone (alphaMSH) 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 alphaMSH 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 Leu144alphaMSH was almost completely abolished due to a dramatically altered binding of Leu144alphaMSH 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.