The melanocortin-1 receptor: red hair and beyond

Arch Dermatol. 2001 Nov;137(11):1477-85. doi: 10.1001/archderm.137.11.1477.


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.

Publication types

  • Review

MeSH terms

  • Agouti Signaling Protein
  • Animals
  • Hair Color / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Melanocyte-Stimulating Hormones / antagonists & inhibitors
  • Mice
  • Polymorphism, Genetic*
  • Pro-Opiomelanocortin / genetics
  • Proteins / genetics
  • Receptors, Corticotropin / genetics*
  • Receptors, Melanocortin
  • Skin Neoplasms / genetics
  • Skin Pigmentation / genetics*


  • Agouti Signaling Protein
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • Pro-Opiomelanocortin
  • Melanocyte-Stimulating Hormones