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The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.


Morgane Baron, Julie Maillet, Marlène Huyvaert, Aurélie Dechaume, Raphaël Boutry, Hélène Loiselle, Emmanuelle Durand, Bénédicte Toussaint, Emmanuel Vaillant, Julien Philippe, Jérémy Thomas, Amjad Ghulam, Sylvia Franc, Guillaume Charpentier, Jean-Michel Borys, Claire Lévy-Marchal, Maïthé Tauber, Raphaël Scharfmann, Jacques Weill, Cécile Aubert, Julie Kerr-Conte, François Pattou, Ronan Roussel, Beverley Balkau, Michel Marre, Mathilde Boissel, Mehdi Derhourhi, Stefan Gaget, Mickaël Canouil, Philippe Froguel, Amélie Bonnefond. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension. Nature medicine. 2019 Nov;25(11):1733-1738

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PMID: 31700171

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