title: Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults.
abstract: Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.
authors.affiliation: Department of Medicine and Research Program in Molecular Medicine, University of Helsinki, FIN-00290 Helsinki, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Valli-Jaakola
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
authors.forename: Laura
authors.initials: L
authors.lastname: Oksanen
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Christian
authors.initials: C
authors.lastname: Bjørbaek
authors.forename: Camilla
authors.initials: C
authors.lastname: Schalin-Jäntti
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D015331:Cohort Studies; D005260:Female; D005387:Finland; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009767:Obesity, Morbid / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D044105:Receptor, Melanocortin, Type 4