title: A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.
abstract: The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-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 beta-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 beta-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 beta-MSH in the control of human energy homeostasis.
authors.affiliation: University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 2XY, United Kingdom.
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.forename: Ben G
authors.initials: BG
authors.lastname: Challis
authors.forename: Darren A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Michael E
authors.initials: ME
authors.lastname: Madonna
authors.forename: Vicki
authors.initials: V
authors.lastname: Wraight
authors.forename: Matthew
authors.initials: M
authors.lastname: Sims
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Julian
authors.initials: J
authors.lastname: Shield
authors.forename: Christine
authors.initials: C
authors.lastname: Burren
authors.forename: Zala
authors.initials: Z
authors.lastname: Ibrahim
authors.forename: Tim
authors.initials: T
authors.lastname: Cheetham
authors.forename: Peter
authors.initials: P
authors.lastname: Swift
authors.forename: Anthea
authors.initials: A
authors.lastname: Blackwood
authors.forename: Chiao-Chien Connie
authors.initials: CC
authors.lastname: Hung
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D044465:White People; D019824:beta-MSH / Q000235:genetics* / Q000378:metabolism
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH