title: Sporadic mutations in melanocortin receptor 3 in morbid obese individuals.
abstract: Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3-6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2+/-5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4+/-2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects.
authors.affiliation: Molecular Biology Laboratory, Istituto Auxologico Italiano, Piancavallo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Mencarelli
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Walker
authors.forename: Sabrina
authors.initials: S
authors.lastname: Maestrini
authors.forename: Luisella
authors.initials: L
authors.lastname: Alberti
authors.forename: Barbara
authors.initials: B
authors.lastname: Verti
authors.forename: Amelia
authors.initials: A
authors.lastname: Brunani
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Petroni
authors.forename: Mariantonella
authors.initials: M
authors.lastname: Tagliaferri
authors.forename: Antonio
authors.initials: A
authors.lastname: Liuzzi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Blasio
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009767:Obesity, Morbid / Q000235:genetics*; D010375:Pedigree; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D044104:Receptor, Melanocortin, Type 3; D000242:Cyclic AMP