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Submitted on September 13, 2005
Accepted on February 14, 2006
Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Essen, Germany; Institute of Human Genetics, GSF-National Research Center for Environment and Health, Genome Analysis Center (GAC), Neuherberg, Germany; Current address: Max-Planck-Institute of Psychiatry, Munich, Germany; Department of Pediatric Endocrinology, Charité Children's Hospital, Humboldt University, Berlin, Germany; Genome Analysis, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI/former IMB), Jena, Germany; Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, Germany; Department of Psychology, Philipps-University of Marburg, Germany; GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; KORA group consists of H.-E. Wichmann (speaker), H. Löwel, C. Meisinger, T. Illig, R. Holle, J. John, and their coworkers, who are responsible for the design and conduct of the KORA studies
* To whom correspondence should be addressed. E-mail: anke.hinney{at}uni-duisburg-essen.de.
Context Autosomal dominant inheritance of mutations in the melanocortin-4 receptor gene (MC4R) is currently regarded as the most relevant genetic cause for extreme obesity, and affects 2-4 percent of extremely obese individuals.
Objective To assess the relevance of MC4R mutations in a German population-based sample.
Design and Setting Mutation screen of the MC4R gene by CE-SSCP and dHPLC.
Participants 4,068 individuals of a German population-based study group (KORA-S4) and 1,003 German obese adults (BMI 
30kg/m2).
Main outcome measures Samples with aberrant CE-SSCP/dHPLC patterns were re-sequenced. Functional studies including agonistic receptor stimulation (NDP-
-, - and 
-MSH) and cell surface expression assays were performed.
Results Sixteen (six novel) coding non-synonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these six heterozygous mutation carriers was obese (BMI 30 kg/m2). In the obese adults, six coding non-synonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function.
Conclusions Our study depicts prevalence, spectrum and functional characterization of MC4R mutations in the German population-based sample KORA-S4. In this epidemiological study group, individuals heterozygous for non-synonymous MC4R mutation alleles entailing impaired function were not obese. Furthermore, non-synonymous MC4R mutations causing impaired receptor function were rare in German obese adults (2 in 1,003 = 0.2%).
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