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Evolutionary Aspects in Evaluating Mutations in the Melanocortin 4 Receptor

Institute of Biochemistry (C.S., T.S., H.R.), Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; Institute of Experimental Pediatric Endocrinology (P.T., H.Br., A.G., H.Bi.), Charité, Universitätsmedizin Berlin, Humboldt University Berlin, 13353 Berlin, Germany; Department of Evolutionary Genetics (C.P.), Institute for Zoo and Wildlife Research, 10252 Berlin, Germany; Institute of Pharmacology and Toxicology (T.G.), Philips University Marburg, 35032 Marburg, Germany; and Department of Organismic and Evolutionary Biology and the Museum of Comparative Zoology (H.R.), Harvard University, Cambridge, Massachusetts 02138

Address all correspondence and requests for reprints to: Holger Römpler, Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany. E-mail: Holger.Roempler{at}medizin.uni-leipzig.de.

More than 70 missense mutations have been identified in the human melanocortin 4 receptor (MC4R), and many of them have been associated with obesity. In a number of cases, the causal link between mutations in MC4R and obesity is controversially discussed. Here, we mined evolution as an additional source of structural information that may help to evaluate the functional relevance of naturally occurring variations in MC4R. The sequence information of more than 60 MC4R orthologs enabled us to identify residues that are important for maintaining receptor function. More than 90% of all inactivating mutations found in obese patients were located at amino acid positions that are highly conserved during 450 million years of MC4R evolution in vertebrates. However, for a reasonable number of MC4R variants, we found no correlation between structural conservation of the mutated position and the reported functional consequence. By reevaluating selected mutations in the MC4R, we demonstrate the usefulness of combining functional and evolutionary approaches.

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