title: Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity.
abstract: Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percentage fat mass: P < 0.001), and had greater plasma leptin (P < 0.0001) and insulin concentrations (P < 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction, and less protein expression. We conclude that diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive body weight gain in children.
authors.affiliation: Unit on Growth and Obesity, National Institutes of Health, 10 Center Dr., Hatfield CRC, Rm 1-3330, MSC 1103, Bethesda, MD 20892-1862, USA.
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.forename: Sharla F
authors.initials: SF
authors.lastname: Young
authors.forename: Greti
authors.initials: G
authors.lastname: Aguilera
authors.forename: Elena
authors.initials: E
authors.lastname: Puricelli
authors.forename: Diane C
authors.initials: DC
authors.lastname: Adler-Wailes
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Sebring
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
mesh_terms: D000273:Adipose Tissue; D000293:Adolescent; D001741:Black or African American / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics; D020738:Leptin / Q000097:blood / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D007328:Insulin; D020738:Leptin; C505392:MC3R protein, human; D044104:Receptor, Melanocortin, Type 3