title: The role of melanocortin 3 receptor gene in childhood obesity.
abstract: OBJECTIVE
  Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear. The objective of this study was to identify genetic variants of the MC3R gene and determine its association with childhood obesity.
  
  
  METHODS
  We screened 201 obese children for MC3R gene mutations with anthropometric measurements, blood tests, feeding behavior, and body composition assessment. We identified three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found in 188 control subjects, and two common polymorphisms Thr6Lys and Val81Ile.
  
  
  RESULTS
  In vitro functional studies of the resultant mutant receptors revealed impaired signaling activity but normal ligand binding and cell surface expression. The heterozygotes demonstrated higher leptin levels and adiposity and less hunger compared with obese control subjects, reminiscent of the MC3R knockout mice. Family studies showed that these mutations may be associated with childhood or early-onset obesity. The common variants Thr6Lys and Val81Ile were in complete linkage disequilibrium, and in vitro studies revealed reduced signaling activity compared with wild-type MC3R. Obese subjects with the 6Lys/81Ile haplotype had significantly higher leptin levels, percentage body fat, and insulin sensitivity, and the causative role of the 6Lys/81Ile variants is supported by the presence of an additive effect in which heterozygotes had an intermediate phenotype compared with homozygotes.
  
  
  CONCLUSIONS
  MC3R mutations may not result in autosomal dominant forms of obesity but may contribute as a predisposing factor to childhood obesity and exert an effect on the human phenotype. Our report supports the role of MC3R in human weight regulation.
authors.affiliation: Department of Paediatrics, National University of Singapore, and the Children's Medical Institute, National University Hospital, Singapore. paeleeys@nus.edu.sg
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.forename: Larry Kok Seng
authors.initials: LK
authors.lastname: Poh
authors.forename: Betty Lay Kee
authors.initials: BL
authors.lastname: Kek
authors.forename: Kah Yin
authors.initials: KY
authors.lastname: Loke
mesh_terms: D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000502:physiology; D002648:Child; D005260:Female; D017930:Genes, Reporter; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000097:blood; D008297:Male; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D010957:Plasmids; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*; D014162:Transfection
chemical_list: D020738:Leptin; C505392:MC3R protein, human; D044104:Receptor, Melanocortin, Type 3