Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity
Christian Vaisse, … , Bernard Guy-Grand, Philippe Froguel
Christian Vaisse, … , Bernard Guy-Grand, Philippe Froguel
Published January 15, 2000
Citation Information: J Clin Invest. 2000;106(2):253-262. https://doi.org/10.1172/JCI9238.
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Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity

Abstract

By integrating an agonist satiety signal, provided by alpha–melanocyte-stimulating hormone (α-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein–coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R–associated obesity is not due to variations in genes for α-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.

Authors

Christian Vaisse, Karine Clement, Emmanuelle Durand, Serge Hercberg, Bernard Guy-Grand, Philippe Froguel

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Figure 1

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Function of obesity-associated MC4-R mutants. (a–d) Activity of the rece...
Function of obesity-associated MC4-R mutants. (a–d) Activity of the receptors is assayed by analyzing their ability to activate expression of a cAMP-induced luciferase fusion gene. Cells stably expressing each receptor and transiently expressing the fusion construct were stimulated for 6 hours with medium alone, increasing amounts of α-MSH or 8Br-cAMP, after which luciferase activity was measured. Data points represent means of five determinations divided by maximal levels of luciferase activity achieved by 1 mM 8Br-cAMP (average of five determinations). Error bars indicate SD. The wild-type receptor activation curve is shown on all graphs for comparison with: (a) the polymorphic Ile251Leu mutation; (b) mutations Thr150Ile, Arg165Trp, Ile170Val, and Ile301Thr; (c) mutation Leu250Gln; (d) the NH2-terminal Thr11Ser and Arg18Cys mutations. The EC50 ± SD is indicated in parentheses for each variant receptor. (e) Binding of [125I] NDP-α-MSH to 293 cells transiently transfected with the wild-type and mutant MC4-Rs. Cells were incubated with a subsaturating amount of [125I]-labeled NDP-α-MSH (200 pM) under conditions described in Methods. The specific binding was derived from the total binding minus nonspecific binding. Data points represent the mean of three independent experiments performed in triplicate and normalized to wild-type binding for each experiment. Error bars indicate SD. (f) Competition-binding assay. Stably transfected cells were incubated with [125I] NDP-α-MSH in the presence of increasing concentrations of α-MSH. All curves are representative of three different experiments and each point is the mean of triplicate values. Error bars indicate SD. The ordinate is expressed as a percentage of total specific binding (Bmax). Curves are fitted using nonlinear regression analysis and a one-site competition model (GraphPad Prism). The IC50 ± SD is indicated in parentheses for each receptor.