title: Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.
abstract: By integrating an agonist satiety signal, provided by alpha-melanocyte-stimulating hormone (alpha-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein-coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R-associated obesity is not due to variations in genes for alpha-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.
authors.affiliation: Centre National de la Recherche Scientifique, UPRES A 8090, Institute of Biology of Lille, Lille, France. vaisse@medicine.ucsf.edu
authors.forename: C
authors.initials: C
authors.lastname: Vaisse
authors.forename: K
authors.initials: K
authors.lastname: Clement
authors.forename: E
authors.initials: E
authors.lastname: Durand
authors.forename: S
authors.initials: S
authors.lastname: Hercberg
authors.forename: B
authors.initials: B
authors.lastname: Guy-Grand
authors.forename: P
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054369:Agouti-Related Protein; D002648:Child; D015331:Cohort Studies; D004435:Eating; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009767:Obesity, Morbid / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D011506:Proteins / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000235:genetics*; D000521:alpha-MSH / Q000378:metabolism
chemical_list: C515198:AGRP protein, human; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D000521:alpha-MSH