title: Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population.
abstract: OBJECTIVE
  Mutations in the melanocortin-4 receptor gene (MC4R) are the most common monogenic form of human obesity. However, the contribution of MC4R mutations to obesity in Chinese has not been investigated. We studied the frequency of MC4R mutations in an obese southern Chinese population and the functional consequences of the novel variants identified.
  
  
  METHODS
  We screened for MC4R mutations in 227 obese [body mass index (BMI) 35.29 +/- 5.75 kg/m2] and 100 lean (BMI 21.57 +/- 0.29 kg/m2) southern Chinese subjects using PCR-direct sequencing. In vitro functional studies, including cell surface expression, ligand binding, and cyclic adenosine monophosphate (cAMP) accumulation, were performed to examine the functional properties of three novel missense mutations.
  
  
  RESULTS
  Apart from two previously reported polymorphisms, V103I and -176 A > C, three novel missense heterozygous variants (Y35C, C40R and M218T) were identified. The polymorphisms -176 A > C and Y35C were detected in both obese and normal subjects with similar frequency. C40R was identified only in an obese subject. Pedigree analysis revealed M218T carriers in both lean and obese subjects. The prevalence of V103I carriers in normal-weight controls was significantly higher than that in obese subjects (5.3%vs. 1.3%, P < 0.05). In vitro functional studies showed that all three novel missense variants have normal functions.
  
  
  CONCLUSIONS
  Two known polymorphisms and three novel variants of the MC4R were identified. No overt functional defects were observed for the three novel MC4R variants, suggesting that they might not be the cause of obesity in variant carriers.
authors.affiliation: Department of Medicine, Li Ka Shing Medical Faculty, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
authors.forename: Bernard M Y
authors.initials: BM
authors.lastname: Cheung
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Grace C N
authors.initials: GC
authors.lastname: Cheung
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002460:Cell Line; D002681:China; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection / Q000379:methods
chemical_list: D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP