title: Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.
abstract: BACKGROUND
  Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype-phenotype correlations.
  
  
  METHODS
  We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant receptors.
  
  
  RESULTS
  Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual signaling capacity had a less severe phenotype.
  
  
  CONCLUSIONS
  Mutations in MC4R result in a distinct obesity syndrome that is inherited in a codominant manner. Mutations leading to complete loss of function are associated with a more severe phenotype. The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans.
authors.affiliation: University Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Lank
authors.forename: Tim
authors.initials: T
authors.lastname: Cheetham
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000595:Amino Acid Sequence; D001823:Body Composition; D002648:Child; D004734:Energy Metabolism; D005260:Female; D005838:Genotype; D006128:Growth; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D006963:Hyperphagia / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000172:deficiency / Q000235:genetics*
chemical_list: D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin