title: Clinical and functional relevance of melanocortin-4 receptor variants in obese German children.
abstract: BACKGROUND
  Variants in the melanocortin-4 receptor (MC4R) gene are the most frequent cause of monogenic obesity. The relevance of MC4R variations with respect to clinical phenotype and biochemical function remains controversial.
  
  
  METHODS
  We sequenced the MC4R gene in 510 overweight/obese children. The clinical phenotype was assessed in a case-control setting matched for age, gender, puberty and body mass index. Identified MC4R variants were functionally characterized in vitro.
  
  
  RESULTS
  The frequency of MC4R variants was 5.3%, with functionally relevant mutations (D(90)N, V(103)I/S(127)L, R(165)W, G(181)D) occurring in 1.2% (confidence interval 0.26-2.15) of our sample. 4.1% were carriers of variants (Y(35)Y, V(103)I, T(112)M, M(200)V, I(251)L) with preserved receptor function in vitro. We did not detect large heterozygous deletions by multiple-ligand probe amplification assay. There were no differences in anthropometric or metabolic parameters between children with loss-of-function mutations and noncarriers. Carriers of the V(103)I or I(251)L variant had higher high-density lipoprotein cholesterol and HbA1c levels than matched noncarriers of MC4R variants.
  
  
  CONCLUSIONS
  In our data set of childhood obesity in central Germany, we identified functionally relevant mutations in the MC4R gene in only 1.2% of the children. There were no major significant phenotypic differences between obese children with and without MC4R mutations. Hence, the diagnosis of genetically caused obesity due to MC4R mutation should be made with caution.
authors.affiliation: Molecular Biochemistry, Institute of Biochemistry, University Hospital for Children and Adolescents, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Melchior
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Jan
authors.initials: J
authors.lastname: Windholz
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002648:Child; D002522:Chlorocebus aethiops; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D014162:Transfection
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4