Identification of Three Novel Genetic Variants in the Melanocortin‐3 Receptor of Obese Children |
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Authors: | Doreen Zegers Sigri Beckers Fenna de Freitas Armand V Peeters Ilse L Mertens Stijn L Verhulst Raoul P Rooman Jean‐Pierre Timmermans Kristine N Desager Guy Massa Luc F van Gaal Wim van Hul |
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Institution: | 1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium;2. Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium;3. Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium;4. Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium;5. Department of Paediatrics, Virga Jesse Hospital, Hasselt, Belgium |
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Abstract: | The melanocortin‐3 receptor (MC3R), a G‐protein‐coupled receptor expressed in the hypothalamus, is a key component of the leptin‐melanocortin pathway that regulates energy homeostasis. It is suggested that an MC3R defect leads to an increased feed efficiency, by which nutrients are partitioned preferentially into fat. In this study, we hypothesized that early‐onset obesity could be induced by mutations in MC3R. To investigate this hypothesis, we screened the entire coding region of the MC3R gene for mutations in obese subjects. A total of 404 overweight and obese children and adolescents, 86 severely obese adults (BMI ≥40 kg/m2), and 150 normal‐weight control adults were included. Besides three synonymous coding variations in the MC3R gene (S69S, L95L, I226I), we were able to identify three novel heterozygous, nonsynonymous, coding mutations (N128S, V211I, L299V) in three unrelated obese children. None of these mutations were found in any of the control subjects. Functional studies assessing localization and signaling properties of the mutant receptors provided proof for impaired function of the L299V mutated receptor, whereas no conclusive evidence for functional impairment of the N128S and V211I mutated receptors could be established. First, these results provide supporting evidence for a role of the MC3R gene in the pathogenesis of obesity in a small subset of patients. Second, they show that caution is called for the interpretation of newly discovered mutations in MC3R. |
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