title: The melanocortin-1 receptor: red hair and beyond.
abstract: Although human pigmentation is genetically complex, to date polymorphism at only 1 locus, the melanocortin-1 receptor (MC1-R), has been associated with physiologic variation in hair and skin color. The MC1-R, a G protein-coupled receptor with 7 transmembrane-spanning domains, plays a key role in determining the type of melanin (eumelanin vs pheomelanin) that is produced within melanocytes. This article begins with an overview of melanocortin receptors, proopiomelanocortin-derived ligands, and the agouti antagonist, with particular focus on their functions in regulating eumelanin and pheomelanin synthesis, including UV-induced melanogenesis. A brief description of mouse-coat-color genetics is then followed by a discussion of human MC1-R variants, which are present in approximately 50% of white populations. We review the increasing evidence that loss-of-function MC1-R mutations largely account for the red hair phenotype in humans (which approximates an autosomal recessive trait) and also have a strong association with fair skin and a decreased ability to tan, with a significant heterozygote effect in individuals without red hair. Finally, we examine recent work showing that loss-of-function MC1-R variants may increase the risk of developing melanoma and nonmelanoma skin cancer beyond their effects on pigmentation phenotype.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA. votavajr@biomed.med.yale.edu
authors.forename: J V
authors.initials: JV
authors.lastname: Schaffer
authors.forename: J L
authors.initials: JL
authors.lastname: Bolognia
mesh_terms: D054366:Agouti Signaling Protein; D000818:Animals; D006200:Hair Color / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009074:Melanocyte-Stimulating Hormones / Q000037:antagonists & inhibitors; D051379:Mice; D011110:Polymorphism, Genetic; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011506:Proteins / Q000235:genetics; D018043:Receptors, Corticotropin / Q000235:genetics*; D044101:Receptors, Melanocortin; D012878:Skin Neoplasms / Q000235:genetics; D012880:Skin Pigmentation / Q000235:genetics*
chemical_list: D054366:Agouti Signaling Protein; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones