Clinical and Functional Relevance of Melanocortin-4 Receptor Variants in Obese German Children

Molecular Biochemistry, Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
Hormone Research in Paediatrics (Impact Factor: 1.57). 11/2012; 78(4):237-246. DOI: 10.1159/000343816
Source: PubMed


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.

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.

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.

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.

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    ABSTRACT: Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population.
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