Loss-of-function mutations in MRAP2are pathogenic in hyperphagic obesity with hyperglycemia and hypertension

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.