Funktionelle Konsequenzen von Mutationen im Melanocortin-4-Rezeptorgen bei adipösen Kindern und Jugendlichen

Der Melanocortin-4-Rezeptor spielt eine zentrale Rolle in der Gewichtsregulation, er vermittelt (indirekt) die anorexigenen Effekte des Leptin, indem er nach Aktivierung eine Einstellung der Nahrungsaufnahme und eine Erhöhung der Stoffwechselrate bedingt. Er ist der Familie der G-Protein-gekoppelte...

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Bibliographic Details
Main Author: Hohmann, Sarah Hortense
Contributors: Gudermann, Thomas (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2006
Online Access:PDF Full Text
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The melanocortin-4 receptor plays an important role within the circuits of body-weight regulation and is responsible for the anorectic effects of leptin. MC4R-Mutations lead to early onset obesity and have been detected in up to 6 % of obese individuals. In this study, we performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or narmal-weight controls. A total of 16 different missense, nonsense and frameshift mutations were found in the obese study group. In vitro cAMP-accumulation-assays revealed that nine of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor functions. Two of the MC4R mutations led to a constitutively active receptor function. As those receptor variants are often retained intracellularly, we also performed a cell-surface ELISA with our samples. Some of our mutations which led to an impaired receptor function in the cAMP-assay also showed reduced cell surface expression in comparison with the expression of the wild type receptor. Cell surface expression of both constitutively active receptors was increased compared to the wild type receptor´s expression.