Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans

  title={Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans},
  author={Paloma Valverde and Eugene Healy and Ian J. Jackson and Jonathan Rees and Anthony J. Thody},
  journal={Nature Genetics},
Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeome-lanin and the black eumelanin, both of which are present in human skin1. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR2, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce… 
The Melanocortin 1 Receptor and the UV Response of Human Melanocytes—A Shift in Paradigm †
Designing potent melanocortin analogs that mimic the effects of α‐MSH as a strategy to prevent skin cancer, particularly in individuals who express MC1R genotypes that reduce but do not abolishMC1R function, or mutations in other melanoma susceptibility genes, such as p16.
Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation.
It is concluded that loss-of-function mutations in the MC1R gene sensitize human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer risk.
Rapid genotyping of melanocortin-1 receptor with use of fluorescence-labeled oligonucleotides.
The melanocortin-1 receptor (MC1R), localized on chromosome 16q24.3, is a G-protein-coupled receptor expressed mostly in melanocytes that may contribute to ultraviolet (UV) radiation-induced skin damage by favoring the synthesis of eumelanin.
Participation of the melanocortin-1 receptor in the UV control of pigmentation.
The cloning of the MC1R gene from human melanocytes and the demonstration that these cells respond to the melanocortins alpha-melanocyte stimulating hormone and adrenocorticotropic hormone with increased proliferation and melanogenesis have renewed the interest in investigation the physiological role of these hormones in regulating human pigmentation.
The melanocortin-1 receptor: red hair and beyond.
The increasing evidence that loss-of-function MC1-R mutations largely account for the red hair phenotype in humans and also have a strong association with fair skin and a decreased ability to tan is reviewed, with a significant heterozygote effect in individuals without red hair.
Red Hair, Light Skin, and UV-Independent Risk for Melanoma Development in Humans.
A key gene which regulates pigmentation in humans is the Melanocortin-1-Receptor, that encodes a seven transmembrane G-protein coupled receptor which regulates cAMP levels in melanocytes, that plausibly provided an evolutionary selective advantage in preventing lethal vitamin D deficiency at high latitude geographic locations.
Pharmacological characterization of loss of function mutations of the human melanocortin 1 receptor that are associated with red hair.
The results provide important pharmacological characterization of common MC1 receptor variants in various world populations and their ability to bind alpha-melanocyte stimulating hormone (MSH) peptides and increase intracellular cAMP.
Melanocortin MC₁ receptor in human genetics and model systems.


Nle4DPhe7 alpha-melanocyte-stimulating hormone increases the eumelanin:phaeomelanin ratio in cultured human melanocytes.
It is demonstrated that Nle4DPhe7 alpha MSH affects melanin type in human melanocytes and a possible mechanism by which this peptide induces skin darkening in man is suggested.
Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor
Agouti protein is used to demonstrate that agouti is a high-affinity antagonist of the MSH receptor and blocks α-MSH stimulation of adenylyl cyclase, the effector through which α- MSH induces eumelanin synthesis.
Effects of melanocyte-stimulating hormone on tyrosinase expression and melanin synthesis in hair follicular melanocytes of the mouse.
It was concluded that, through its actions on the enzyme tyrosinase, alpha-MSH is able to switch the synthesis of phaeomelanin to that of eumelananin in hair follicular melanocytes.
Pheomelanin as well as eumelanin is present in human epidermis.
The present findings could be particularly significant in view of recent suggestions that pheomelanin, rather than protecting the skin against UV radiation, may actually contribute to UV-induced skin damage.
Effects of melanin-induced free radicals on the isolated rat peritoneal mast cells.
The finding that mast cells release histamine when irradiated in the presence of RHM suggests that the immediate and late-phase reactions seen in sunburn may in part be due to the release of mediators from these cells.
The cloning of a family of genes that encode the melanocortin receptors.
The murine and human MSH receptors (MSH-Rs) and a human ACTH receptor (ACTH-R) were cloned and define a subfamily of receptors coupled to guanine nucleotide-binding proteins that may include the cannabinoid receptor.
Molecular cloning of a novel melanocortin receptor.
Major locus for red hair color linked to MNS blood groups on chromosome 4
Red hair color (RHC) was studied in a Danish material of normal families that was tested earlier for 65 marker Systems. We found 4.85% of the parents to be red‐baired or to have been so early in
Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis
Point mutations in TGM1, the gene encoding transglutaminase 1, are identified in two of the multiplex LI families used in the linkage study and it is hypothesized that these mutations adversely affect formation of crosslinks essential in production of cornified cell envelopes and a normal stratum corneum layer of the skin.