IntroductionThe genetic basis for human obesity is largely unknown. Recently mutations in the gene encoding the melanocortin 4 receptor (MC4R) are reported to be associated with the most common monogenic form of obesity in both humans and rodents. The MC4R belongs to the large superfamily of G protein-coupled receptors (GPCRs). It is found that 2-6% of severely obese individuals are heterozygous for functionally relevant non-synonymous, frameshift and nonsense MC4R mutations. Up to now most screening for MC4R mutations have been done in Caucasian individuals. Only three studies involved individuals from Asia. Thus the impact of MC4R mutations on the development of obesity in Asian populations is currently unknown. The frequency of MC4R mutations in Chinese population has not been reported. ObjectiveTo search for mutations in the MC4R in obese and normal weight Chinese children and adolescents.Materials and MethodsThree hundred Chinese children and adolescents, including 200 obese and 100 normal weight individuals, were evaluated. The coding region of the MC4R gene was amplified by PCR and sequenced. In the obese group, oral glucose tolerance tests (OGTT) were performed by ingestion of 1.75g/kg glucose (maximum 75g) after an overnight fast and subsequent measurement of plasma glucose levels by the glucose oxidase method Serum insulin levels were determined by radioimmunity assay. And plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and cholesterol (CHOL) were measured by routine laboratory test. The whole body insulin sensitivity index was calculated. Results(1) In obese individuals, we detected two novel heterozygous non-synonymous mutations (c.496G>A, resulting in Val166Ile;c.929G>A, resulting in Arg310Lys) and a novel heterozygous nonsense mutation (c.831T>A, resulting in a premature stop codon Cys277Stop). In both obese individuals and the controls, a novel heterozygous non-synonymous mutation (c.68T>G, resulting in Leu23Arg, 0.5% and 1%, respectively) and the Val103Ile polymorphism (c.307G>A, 3% and 2%, respectively) were found.(2) There was no difference in ALT, AST, TG, CHOL and WBISI between obese individuals with and without mutation. The prevalence for heterozygous MC4R mutations was 1.5% in the obese.Conclusions(1) Two novel heterozygous non-synonymous mutations (Vall66Ile;Arg310Lys) and a novel heterozygous nonsense mutation (Cys277Stop) were detected in Chinese obese chlidren.(2) Leu23Arg variant might be a polymorphism in the Chinese population.