The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, α- and β-MSH, the majority of attention has focused on α-MSH, partly reflecting the absence of β-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding β-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type β-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for β-MSH in the control of human energy homeostasis.
Bibliographical noteFunding Information:
Y.S.L. was supported by an International Fellowship from The Agency for Science, Technology and Research, Singapore. This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., and S.O.R.) and the Medical Research Council (S.O.R., N.J.W., and P.F.) and the U.S. National Institutes of Health (G.L.M., DK64265). We are indebted to the patients and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS).
Copyright 2008 Elsevier B.V., All rights reserved.