title: Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis.
abstract: BACKGROUND
  Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity.
  
  
  OBJECTIVE
  The aims of this study were the following: 1) to estimate the prevalence of MC4R mutations in obese Czech children; 2) to evaluate phenotypic features of the mutation carriers; 3) to compare weight, height, and body mass index of MC4R mutation carriers with noncarriers in longitudinal studies; 4) to determine the effect of a weight management program among MC4R mutation carriers; and 5) to perform a functional analysis of a novel variant.
  
  
  METHODS
  We analyzed the coding region of MC4R in a cohort of 289 Czech children and adolescents with early-onset obesity by direct sequencing. Information on weight, height, body mass index, baseline biochemical data, and a weight loss follow-up study was obtained. In vitro functional analysis of one novel variant was performed.
  
  
  RESULTS
  We identified six different mutations in seven probands: one novel missense mutation Cys84Arg and five previously reported variants, Arg7Cys, Ser19fsdelA, Phe51Leu, Ser127Leu, and Gly181Asp. The Gly181Asp variant was detected in one homozygous carrier from unrelated parents. None of the mutation carriers fulfilled the MC4R syndrome criteria. A comparison of anthropometrics in mutation carriers and noncarriers during 13 yr of follow-up did not reveal any significant differences. MC4R mutation carriers exhibited a similar ability to lose weight as obese noncarriers. The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R.
  
  
  CONCLUSIONS
  Among obese Czech children, we found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations and showed a similar response to diet management of MC4R mutation carriers and noncarriers.
authors.affiliation: Department of Pediatrics and Center for Research of Diabetes, Metabolism, and Nutrition, Third Faculty of Medicine, Charles University, 100 34 Prague 10, Czech Republic. ihainer@hotmail.com
authors.forename: Irena
authors.initials: I
authors.lastname: Hainerová
authors.forename: Lesli H
authors.initials: LH
authors.lastname: Larsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Marie
authors.initials: M
authors.lastname: Finková
authors.forename: Vojtech
authors.initials: V
authors.lastname: Hainer
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000293:Adolescent; D000328:Adult; D001827:Body Height / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation; D009765:Obesity / Q000178:diet therapy / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000502:physiology*; D015431:Weight Loss / Q000502:physiology*
chemical_list: D044105:Receptor, Melanocortin, Type 4