A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.
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.
Lee
Yung Seng
YS
University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 2XY, United Kingdom.
Challis
Ben G
BG
Thompson
Darren A
DA
Yeo
Giles S H
GS
Keogh
Julia M
JM
Madonna
Michael E
ME
Wraight
Vicki
V
Sims
Matthew
M
Vatin
Vincent
V
Meyre
David
D
Shield
Julian
J
Burren
Christine
C
Ibrahim
Zala
Z
Cheetham
Tim
T
Swift
Peter
P
Blackwood
Anthea
A
Hung
Chiao-Chien Connie
CC
Wareham
Nicholas J
NJ
Froguel
Philippe
P
Millhauser
Glenn L
GL
O'Rahilly
Stephen
S
Farooqi
I Sadaf
IS
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
C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH