Variants of the MRAP2 gene have already been described as causing monogenic obesity. However, the precise functional consequences of these variants have remained unclear. Now a large study published in Nature Medicine provides new insights. Researchers from France performed whole-exome sequencing in 9,418 adults, children, and adolescents and identified 23 rare MRAP2 variants that were associated with an increased obesity risk. 14 of the variants were novel. Further functional experiments showed that seven variants resulted in a loss of MRAP2 protein function. The majority (75%) of the obese or overweight persons carrying one of these loss-of-function variants reported abnormal eating behavior including overeating. Additionally, most of the carriers presented with hyperglycemia and hypertension. This is notable because in other forms of monogenic obesity with overeating described so far, due for example by mutations in MCR4, patients present with low blood pressure and normal glucose tolerance.

MRAP2, or melanocortin-2 receptor accessory protein 2, increases the activity of another protein, MC4R (melanocortin 4 receptor). Mutations in MC4R have been shown to be the most frequent cause of monogenic obesity. In the functional workup performed in the current study, cells with MRAP2 mutations showed a decrease in MC4R signaling. Since deficiency in MRAP2 partly impacts the MC4R signaling pathway, the authors thus suggest that administration of an MC4R agonist might be a potential treatment option.