This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hinney, A. Articles by Hebebrand, J. Search for Related Content PubMed PubMed Citation Articles by Hinney, A. Articles by Hebebrand, J. Related Collections Neuroendocrinology and Pituitary Metabolism Obesity

Prevalence, Spectrum, and Functional Characterization of Melanocortin-4 Receptor Gene Mutations in a Representative Population-Based Sample and Obese Adults from Germany

Department of Child and Adolescent Psychiatry (A.H., K.R., J.H.), Rheinische Kliniken Essen, University of Duisburg-Essen, D-45147 Essen, Germany; Institutes of Human Genetics (T.B., P.L., T.M.) and Epidemiology (C.V., T.I., H.W.), GSF-National Research Center for Environment and Health, Genome Analysis Center, D-85764 Neuherberg, Germany; Department of Pediatric Endocrinology (P.T., H.Br., H.Bi.), Charité Children’s Hospital, Humboldt University, D-13353 Berlin, Germany; Genome Analysis (K.R., M.P.), Leibniz Institute for Age Research - Fritz Lipmann Institute, D-07745 Jena, Germany; and Institute of Medical Biometry and Epidemiology (A.S., T.T.N., H.S.) and Department of Psychology (P.S., W.R.), Philipps-University of Marburg, D-35037 Marburg, Germany

Address all correspondence and requests for reprints to: Dr. A. Hinney, Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Virchowstrasse 174, 45147 Essen, Germany. 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% of extremely obese individuals.

Objective: Our objective was to assess the relevance of MC4R mutations in a German population-based sample.

Design and Setting: We conducted a mutation screen of the MC4R gene by capillary electrophoresis-based single-strand conformation polymorphism analysis and denaturing HPLC.

Participants: Subjects included 4068 individuals of a German population-based study group [Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA-S4); i.e. Cooperative Health Research in the Region of Augsburg] and 1003 German obese adults (body mass index 30 kg/m²).

Main Outcome Measures: Samples with aberrant capillary electrophoresis-based single-strand conformation polymorphism analysis/denaturing HPLC patterns were resequenced. Functional studies including agonistic receptor stimulation (Nle-D-Phe--, -, and ß-MSH) and cell surface expression assays were performed.

Results: Sixteen (six novel) coding nonsynonymous 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 (body mass index 30 kg/m²). In the obese adults, six coding nonsynonymous 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 nonsynonymous MC4R mutation alleles entailing impaired function were not obese. Furthermore, nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (two in 1003 = 0.2%).

This article has been cited by other articles:

				M. A. Calton, B. A. Ersoy, S. Zhang, J. P. Kane, M. J. Malloy, C. R. Pullinger, Y. Bromberg, L. A. Pennacchio, R. Dent, R. McPherson, et al. Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study Hum. Mol. Genet., March 15, 2009; 18(6): 1140 - 1147. [Abstract] [Full Text] [PDF]

				G. V. Kryukov, A. Shpunt, J. A. Stamatoyannopoulos, and S. R. Sunyaev Power of deep, all-exon resequencing for discovery of human trait genes PNAS, March 10, 2009; 106(10): 3871 - 3876. [Abstract] [Full Text] [PDF]

				J. Krakoff, L. Ma, S. Kobes, W. C. Knowler, R. L. Hanson, C. Bogardus, and L. J. Baier Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant Diabetes, December 1, 2008; 57(12): 3267 - 3272. [Abstract] [Full Text] [PDF]

				F. Stutzmann, K. Tan, V. Vatin, C. Dina, B. Jouret, J. Tichet, B. Balkau, N. Potoczna, F. Horber, S. O'Rahilly, et al. Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees Diabetes, September 1, 2008; 57(9): 2511 - 2518. [Abstract] [Full Text] [PDF]

				P. M. Conn, A. Ulloa-Aguirre, J. Ito, and J. A. Janovick G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo Pharmacol. Rev., September 1, 2007; 59(3): 225 - 250. [Abstract] [Full Text] [PDF]

				I. Hainerova, L. H. Larsen, B. Holst, M. Finkova, V. Hainer, J. Lebl, T. Hansen, and O. Pedersen Melanocortin 4 Receptor Mutations in Obese Czech Children: Studies of Prevalence, Phenotype Development, Weight Reduction Response, and Functional Analysis J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3689 - 3696. [Abstract] [Full Text] [PDF]

				F. Stutzmann, V. Vatin, S. Cauchi, A. Morandi, B. Jouret, O. Landt, P. Tounian, C. Levy-Marchal, R. Buzzetti, L. Pinelli, et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene Hum. Mol. Genet., August 1, 2007; 16(15): 1837 - 1844. [Abstract] [Full Text] [PDF]

				B. M. Kublaoui and A. R. Zinn MC4R Mutations--Weight before Screening! J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1671 - 1672. [Full Text] [PDF]