title: Melanocortin-3-receptor gene variants in morbid obesity.
abstract: BACKGROUND
  Linkage and knock-out mice studies suggest that the melanocortin-3-receptor (MC3R) is a candidate gene for obesity.
  
  
  OBJECTIVE
  To evaluate whether MC3R mutations underlie morbid obesity.
  
  
  METHODS
  MC3R coding and 5(')-flanking regions were sequenced in 48 subjects and the detected variants genotyped in 252 morbidly obese (BMI>/=40 kg/m(2)) Finns. Gel shifts were used to examine whether a mutation in the putative promoter alters GATA-factor binding.
  
  
  RESULTS
  Three common MC3R variants were found: a 17C>A variant, changing Thr6-->Lys in 16%, a 241G>A variant changing Val81-->Ile in 15%, and a -239A>G substitution in the GATA binding site in 21% of the subjects. Four other variants were detected in the 5(') flanking region. Frequencies of the three common variants did not differ between obese and contol subjects. Among the obese, the 17C>A and 241G>A variants were coinherited and associated with increased insulin-glucose ratios (P<0.05) and leptin levels (P<0.05). GATA-4 bound efficiently to wild type oligonucleotide, but only weakly to the oligonucleotide with the -239A>G mutation.
  
  
  CONCLUSIONS
  MC3R gene variants are common and do not explain human morbid obesity. These variants associated with subtle changes in onset of weight gain, hyperleptinemia and insulin-glucose ratios. The -239A>G mutation abolishes binding of GATA-4 to the MC3R promoter region.
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland. camilla.scalin-jantti@hus.fi
authors.forename: C
authors.initials: C
authors.lastname: Schalin-Jäntti
authors.forename: K
authors.initials: K
authors.lastname: Valli-Jaakola
authors.forename: L
authors.initials: L
authors.lastname: Oksanen
authors.forename: E
authors.initials: E
authors.lastname: Martelin
authors.forename: K
authors.initials: K
authors.lastname: Laitinen
authors.forename: T
authors.initials: T
authors.lastname: Krusius
authors.forename: P
authors.initials: P
authors.lastname: Mustajoki
authors.forename: M
authors.initials: M
authors.lastname: Heikinheimo
authors.forename: K
authors.initials: K
authors.lastname: Kontula
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009767:Obesity, Morbid / Q000235:genetics*; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D014157:Transcription Factors