title: Novel melanocortin 4 receptor gene mutations in severely obese children.
abstract: OBJECTIVE
  Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children.
  
  
  METHODS
  We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing.
  
  
  RESULTS
  We identified three mutations in three subjects: 4 bp deletion from nucleotides 631-634 (c.631-634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1.32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non-obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early-onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity.
  
  
  CONCLUSIONS
  MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.
authors.affiliation: Department of Paediatrics, National University of Singapore, and The Children's Medical Institute, National University Hospital, Singapore. paeleeys@nus.edu.sg
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.forename: Larry Kok Seng
authors.initials: LK
authors.lastname: Poh
authors.forename: Betty Lay Kee
authors.initials: BL
authors.lastname: Kek
authors.forename: Kah Yin
authors.initials: KY
authors.lastname: Loke
mesh_terms: D016022:Case-Control Studies; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D005820:Genetic Testing; D006801:Humans; D008297:Male; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012720:Severity of Illness Index; D012846:Singapore
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4