title: [Prevalence of melanocortin 4 receptor (MC4R) mutations and polymorphismsin consecutively ascertained obese children and adolescents from a pediatric health care utilization population].
abstract: BACKGROUND
  The prevalence of childhood obesity is steadily increasing. Weight regulation and food intake are subject to complex regulatory mechanisms. The leptinergic-melanocortinergic system is known to be of major importance.
  
  
  OBJECTIVE
  Identification of mutations in the melanocortin 4 receptor gene (MC4R) and of phenotypic effects of detected mutations in German obese children and adolescents. Family specific and cardiovascular risk factors were also analysed.
  
  
  METHODS
  Consecutive ascertainment of 90 obese children and adolescents with a medium BMI SDS of + 2.6, age range 3 to 16 years.
  
  
  METHODS
  Mutation screen within the MC4R was carried out by denaturing high performance liquid chromatography (dHPLC) and re-sequencing of samples with aberrant dHPLC patterns. Eating behaviour and obesity-associated diseases within the families were evaluated by semi-structured interviews. Metabolic evaluation included: oral glucose tolerance test (OGTT, WHO criteria) for calculation of insulin resistance (Homeostasis Model Assessment, HOMA) and insulin sensitivity index (ISI), lipid panel for lipid status, blood pressure measurement and abdominal ultrasound.
  
  
  RESULTS
  Three patients were heterozygous MC4R mutation carriers (Thr112Met, Ala175Thr and Gly181Asp). Gly181Asp leads to a complete loss of function; whereas Thr112Met and Ala175Thr lead to a reduced receptor function. The patients with heterozygous MC4R mutations had BMIs, cholesterol levels and waist to hip ratios (W/H) that did not differ from the rest of our study group. The overall occurrence of hypertriglyceridemia (34 %) and hypercholesterinemia (22 %) was correlated with the W/H-ratio. The overall incidence of impaired glucose tolerance was 12 %. In those with a normal glucose tolerance 68 % already had an increased HOMA (mean 3.12; reference value < 1.9) and decreased ISI (mean 4.3; reference value > 7.2). The patients with MC4R mutations had a normal glucose tolerance with similar HOMA and ISI values compared to the rest of the patients. Hypertension was found in 24 % of all cases and blood pressure was correlated with BMI (r+ 0.8). None of the patients with MC4R mutations were hypertensive. Leptin levels did not discriminate between patients with MC4R mutations and the other patients. Five patients harboured one of the MC4R polymorphisms (Val103Ile, Ile251Leu). These were phenotypically indistinguishable from the individuals without MC4R variants.
  
  
  CONCLUSIONS
  We detected MC4R mutations (Thr112Met, Ala175Thr and Gly181Asp) in 3.3 % and MC4R polymorphisms (Val103Ile, Ile251Leu) in 5.5 % of the analysed obese children and adolescents, respectively. The patients with MC4R mutations did not show a higher metabolic risk compared to obese children and adolescents without mutations. However the total study group is prone to an increased risk for developing metabolic and cardiovascular diseases.
authors: Center of Child and Adolescent Medicine, Justus-Liebig-University of Giessen, Giessen, Germany.
authors: U A
authors: UA
authors: Zakel
authors: S A
authors: SA
authors: Wudy
authors: M
authors: M
authors: Heinzel-Gutenbrunner
authors: T
authors: T
authors: Görg
authors: H
authors: H
authors: Schäfer
authors: L
authors: L
authors: Gortner
authors: W F
authors: WF
authors: Blum
authors: J
authors: J
authors: Hebebrand
authors: A
authors: A
authors: Hinney
mesh_terms: D000293:Adolescent; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D006580:Genetic Carrier Screening; D005951:Glucose Tolerance Test; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics; D015228:Hypertriglyceridemia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012306:Risk; D012307:Risk Factors; D049629:Waist-Hip Ratio
chemical_list: D044105:Receptor, Melanocortin, Type 4