ECE2016 Oral Communications Obesity (5 abstracts)
Functional characterization of naturally occurring mutations in the melanocortin receptor accesory protein 2 (MRAP2)
Heike Biebermann 1 , Laura Schonnop 2 , Nikolas Herrfurth 2 , Anna-Lena Volckmar 2 , Anne Müller 1 , Triinu Peters 2 , Stephan Herpertz 3 , Jochen Antel 2 , Johannes Hebebrand 2 , Gunnar Kleinau 1 & Anke Hinney 2
1Charité Universitätsmedizin Berlin, Institut für Experimentelle Pädiatrische Endokrinologie, Berlin, Germany; 2Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 3Department of Psychosomatic Medicine and Psychotherapy, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany.
Introduction: The melanocortin 4 receptor (MC4R) is the most important hypothalamic expressed G protein coupled receptor in weight regulation. Mutations in the MC4R are the most frequent genetic cause of obesity. Recently an accessory protein of the MC4R (melanocortin receptor accessory protein 2, MRAP2) was discovered that was found to play a role in body weight regulation. MRAP2 deficient mice develop early-onset obesity. The mechanisms of disturbed weight regulation is potentially a role of MRAP2 at MC4R function. However, naturally occurring mutant MRAP2 were yet not been identified and the impact of MRAP variants for regulation of signaling properties of the MC4R were not characterized so far.
Methods: Mutational screening and determination of cAMP accumulation by AlphaScreen technology.
Results: By screening for MRAP2 mutations in nearly 200 obese children and over 180 lean controls, we detected three non-synonymous MRAP2 variants which are all heterozygous in the patients. For functional characterization of the three non-synonymous MRAP2 variants, we established an experimental procedure to characterize MRAP2 mediated effects on MC4R signaling. Characterization of the three mutations revealed for only for one MRAP2 variant a significant decrease in MC4R signaling in comparison to MC4R signaling in presence of MRAP2 wild-type. We also tested different transfection ratios between MC4R/MRAP2 and determined MC4R signaling after alpha-MSH challenge. This experiment demonstrated that the impact of MRAP2 on MC4R function is dependent on the ratio between MC4R to MRAP2, which can be modified by mutations in MRAP2 pointing to the fact that MRAP2 might act in a dimeric state.
Conclusion: For the first time we describe a mode of action for the MRAP2/MC4R complex and provide hints for a relevance of this complex for body weight regulation in humans.
Volume 41
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Endocrine Abstracts
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