| Literature DB >> 16459314 |
Yung Seng Lee1, Ben G Challis, Darren A Thompson, Giles S H Yeo, Julia M Keogh, Michael E Madonna, Vicki Wraight, Matthew Sims, Vincent Vatin, David Meyre, Julian Shield, Christine Burren, Zala Ibrahim, Tim Cheetham, Peter Swift, Anthea Blackwood, Chiao-Chien Connie Hung, Nicholas J Wareham, Philippe Froguel, Glenn L Millhauser, Stephen O'Rahilly, I Sadaf Farooqi.
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.Entities:
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Year: 2006 PMID： 16459314 DOI： 10.1016/j.cmet.2006.01.006
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287