title: A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity.
abstract: This study targeted the identification of mutations of melanocortin-4 receptor gene (MC4R) in obese children. Fifty-one unrelated probands with early onset severe obesity (body mass index (BMI) > 99th percentile; 21 girls, mean age 10.6 +/- 3.6 years) were analyzed for nucleotide variations in the MC4R coding region, by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. MC4R variants were detected in three patients: the known I169S variant was found in heterozygote state in two patients and a novel heterozygous Y302F mutation was detected in one 12-year-old girl (BMI = 34 kg/m(2), BMI z-score 2.7) who has been overweight since the second year of life and suffered from hyperinsulinemia (at the age of 12: fasting insulin 45 mU/ml, after oral glucose load max. 300 mU/ml). The mutation also appears in the father, although both parents are obese (BMI father: 30.2 kg/m(2); mother: 31.9 kg/m(2)). This novel mutation is located in the functionally important NPXXY motif of the seventh transmembrane domain of the receptor. Functional characterization revealed reduction in cell surface expression and an alteration in signal transduction properties. These results add to the growing list of loss-of-function MC4R mutations in early onset obese patients and suggest an orexigenic effect of novel Y302F mutation.
authors.affiliation: Division of Endocrinology, Seattle Children's Hospital Research Institute, Seattle, WA 98101, USA. christian.roth@seattlechildrens.org
authors.forename: Christian L
authors.initials: CL
authors.lastname: Roth
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Joachim
authors.initials: J
authors.lastname: Woelfle
authors.forename: Zhen-Chuan
authors.initials: ZC
authors.lastname: Fan
authors.forename: Harald
authors.initials: H
authors.lastname: Brumm
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D004734:Energy Metabolism / Q000235:genetics; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4