Human Molecular Genetics, 2003, Vol. 12, No. 5 561-574
© 2003 Oxford University Press
Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms
1Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2XY, UK and 2University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, UK
Received November 5, 2002; Revised December 7, 2002; Accepted December 19, 2002
Mutations in the melanocortin-4 receptor gene (MC4R) represent the commonest monogenic cause of human obesity. However, information regarding the precise effects of such mutations on receptor function is very limited. We examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the nine missense mutants studied, four were completely unable to generate cAMP in response to ligand and five were partially impaired. Four showed evidence of impaired cell surface expression and six of reduced binding affinity for ligand. One mutation in the C-terminal tail, I316S, showed reduced affinity for 
-MSH but retained normal affinity for the antagonist AgRP. None of the mutations inhibited signaling through co-transfected wild-type receptors. Thus, in the most comprehensive study to date of the functional properties of naturally occurring MC4R mutations we have (1) established that defective expression on the cell surface is a common mechanism impairing receptor function, (2) identified mutations which specifically affect ligand binding affinity thus aiding the definition of receptor structure-function relationships, (3) provided evidence against the notion that these receptor mutants act as dominant-negatives, and (4) identified a potentially novel molecular mechanism of receptor dysfunction whereby a mutation alters the relative affinities of a receptor for its natural agonist versus antagonist.
* To whom correspondence should be addressed. Tel: +44 1223762620; Fax: +44 1223762323; Email: gyeo{at}hgmp.mrc.ac.uk
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