| Title: |
Loss-of-function mutations in MRAP2are pathogenic in hyperphagic obesity with hyperglycemia and hypertension |
| Authors: |
Baron, Morgane, Maillet, Julie, Huyvaert, Marlène, Dechaume, Aurélie, Boutry, Raphaël, Loiselle, Hélène, Durand, Emmanuelle, Toussaint, Bénédicte, Vaillant, Emmanuel, Philippe, Julien, Thomas, Jérémy, Ghulam, Amjad, Franc, Sylvia, Charpentier, Guillaume, Borys, Jean-Michel, Lévy-Marchal, Claire, Tauber, Maïthé, Scharfmann, Raphaël, Weill, Jacques, Aubert, Cécile, Kerr-Conte, Julie, Pattou, François, Roussel, Ronan, Balkau, Beverley, Marre, Michel, Boissel, Mathilde, Derhourhi, Mehdi, Gaget, Stefan, Canouil, Mickaël, Froguel, Philippe, Bonnefond, Amélie |
| Source: |
Nature Medicine; November 2019, Vol. 25 Issue: 11 p1733-1738, 6p |
| Abstract: |
The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2mutations have been described in people with obesity1–3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2in 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 MRAP2variants 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 MRAP2might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets. |
| Database: |
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