title: Molecular genetics of human obesity-associated MC4R mutations.
abstract: Heterozygous coding mutations in the melanocortin 4 receptor (MC4R) are implicated in 1 to 6% of early onset or severe adult obesity cases. To better address the problem of the genotype:phenotype relationship within this specific form of obesity, we systematically studied the functional characteristics of 50 different obesity-associated MC4R mutations. Structure modeling of MC4R indicates that obesity-associated MC4R mutations are not localized in a single domain of the protein. We developed a flow cytometry-based assay to compare cell membrane expression of obesity-associated MC4R mutants. Using this assay, we demonstrate that over 54% of the obesity-associated MC4R mutations impair the membrane expression of MC4R. All other mutations impair the basal constitutive activity and/or the EC(50) for the physiological agonist alpha-MSH as measured in a cAMP- dependent luciferase assay. The extent of the alterations in receptor activity ranges from a total suppression of MC4R activation in response to alpha-MSH to a mild alteration of the basal constitutive activity of the receptor. Since most patients are heterozygous for MC4R mutations, these data indicate that a small decrease in overall MC4R activity can cause obesity, strongly supporting the hypothesis that the MC4R is a critical component of the adipostat in humans.
authors.affiliation: Department of Medicine, University of California, San Francisco, California 94143, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Lubrano-Berthelier
authors.forename: Martha
authors.initials: M
authors.lastname: Cavazos
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dubern
authors.forename: Astrid
authors.initials: A
authors.lastname: Shapiro
authors.forename: Catherine L E
authors.initials: CL
authors.lastname: Stunff
authors.forename: Sumei
authors.initials: S
authors.lastname: Zhang
authors.forename: Franck
authors.initials: F
authors.lastname: Picart
authors.forename: Cedric
authors.initials: C
authors.lastname: Govaerts
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougneres
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Christian
authors.initials: C
authors.lastname: Vaisse
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D008967:Molecular Biology; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017433:Protein Structure, Secondary; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D000242:Cyclic AMP