title: Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor.
abstract: 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 re-evaluating selected mutations in the MC4R, we demonstrate the usefulness of combining functional and evolutionary approaches.
authors.affiliation: Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stäubert
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarnow
authors.forename: Harald
authors.initials: H
authors.lastname: Brumm
authors.forename: Christian
authors.initials: C
authors.lastname: Pitra
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Holger
authors.initials: H
authors.lastname: Römpler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D009765:Obesity / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D014714:Vertebrates
chemical_list: D044105:Receptor, Melanocortin, Type 4