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- Title
Molecular Genetics of Human Obesity-Associated MC4R Mutations.
- Authors
LUBRANO-BERTHELIER, CECILE; CAVAZOS, MARTHA; DUBERN, BEATRICE; SHAPIRO, ASTRID; STUNFF, CATHERINE; ZHANG, SUMEI; PICART, FRANCK; GOVAERTS, CEDRIC; FROGUEL, PHILIPPE; BOUGNÈRES, PIERRE; CLEMENT, KARINE; VAISSE, CHRISTIAN
- Abstract
A bstract: 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 EC50 for the physiological agonist α-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 α-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.
- Publication
Annals of the New York Academy of Sciences, 2003, Vol 994, Issue 1, p49
- ISSN
0077-8923
- Publication type
Article
- DOI
10.1111/j.1749-6632.2003.tb03161.x