Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor.

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.

[1]  Helgi B. Schiöth,et al.  Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes , 2005, Peptides.

[2]  H. Mergen,et al.  A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. , 2001, The Journal of clinical endocrinology and metabolism.

[3]  S. Talbot,et al.  A phylogeny of the bears (Ursidae) inferred from complete sequences of three mitochondrial genes. , 1996, Molecular phylogenetics and evolution.

[4]  C. Donahue,et al.  Cell Surface Expression of the Melanocortin-4 Receptor Is Dependent on a C-terminal Di-isoleucine Sequence at Codons 316/317* , 2003, The Journal of Biological Chemistry.

[5]  Robert Fredriksson,et al.  Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes. , 2004, The Biochemical journal.

[6]  Zhimin Xiang,et al.  Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. , 2006, Biochemistry.

[7]  S. O’Rahilly,et al.  A frameshift mutation in MC4R associated with dominantly inherited human obesity , 1998, Nature Genetics.

[8]  E. Snyder,et al.  Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. , 2002, The Journal of clinical endocrinology and metabolism.

[9]  T. Gudermann,et al.  V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms , 1998, Human mutation.

[10]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[11]  D. Segaloff,et al.  Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. , 2005, The Journal of clinical endocrinology and metabolism.

[12]  S. O’Rahilly,et al.  Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. , 2003, Human molecular genetics.

[13]  T. Schöneberg,et al.  Mutationally Induced Disulfide Bond Formation within the Third Extracellular Loop Causes Melanocortin 4 Receptor Inactivation in Patients with Obesity* , 2003, Journal of Biological Chemistry.

[14]  T. Schöneberg,et al.  The Structural Evolution of a P2Y-like G-protein-coupled Receptor* , 2003, Journal of Biological Chemistry.

[15]  D. Segaloff,et al.  Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. , 2003, Endocrinology.

[16]  O. Pedersen,et al.  Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. , 2005, The Journal of clinical endocrinology and metabolism.

[17]  F. Contaldo,et al.  Six novel mutations in the proopiomelanocortin and melanocortin receptor 4 genes in severely obese adults living in southern Italy. , 2005, Clinical chemistry.

[18]  R. Cone.  Anatomy and regulation of the central melanocortin system , 2005, Nature Neuroscience.

[19]  K. Sangkuhl,et al.  Nephrogenic diabetes insipidus caused by mutation of Tyr205: A key residue of V2 vasopressin receptor function , 2005, Human mutation.

[20]  M. Rothschild,et al.  Functional and phylogenetic analyses of a melanocortin-4 receptor mutation in domestic pigs. , 2004, Domestic animal endocrinology.

[21]  C. Londos,et al.  A highly sensitive adenylate cyclase assay. , 1974, Analytical biochemistry.

[22]  Robert Fredriksson,et al.  One melanocortin 4 and two melanocortin 5 receptors from zebrafish show remarkable conservation in structure and pharmacology , 2002, Journal of neurochemistry.

[23]  K. Clément,et al.  Molecular Genetics of Human Obesity‐Associated MC4R Mutations , 2003, Annals of the New York Academy of Sciences.

[24]  Thomas Gudermann,et al.  Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. , 2003, The Journal of clinical endocrinology and metabolism.

[25]  K. Clément,et al.  A frameshift mutation in human MC4R is associated with a dominant form of obesity , 1998, Nature Genetics.

[26]  Katrin Sangkuhl,et al.  Mutant G-protein-coupled receptors as a cause of human diseases. , 2004, Pharmacology & therapeutics.