title: Variants of the melanocortin-1 receptor: do they matter clinically?
abstract: The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane receptor primarily expressed on melanocytes and melanoma cells. Single nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause red hair, fair skin and are associated with melanoma and keratinocyte-derived skin cancer development. Activation of wild-type (WT) MC1R in skin assists cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of MC1R variants may have related to improved cutaneous vitamin D synthesis and higher birthweight reported with certain MC1R variants. Reduced photoprotection secondary to MC1R dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA repair, effects on cell proliferation and possibly immunological parameters), leading to clonal expansion of mutated cells within skin and subsequent carcinogenesis. Recent investigations suggest an association between MC1R genotype and vitiligo, with preliminary evidence that a MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk.
authors.affiliation: Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, UK; Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Ciara
authors.initials: C
authors.lastname: Haddadeen
authors.forename: Chester
authors.initials: C
authors.lastname: Lai
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Cho
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
mesh_terms: D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008027:Light; D008544:Melanocytes / Q000187:drug effects; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation; D010859:Pigmentation Disorders / Q000235:genetics / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D012880:Skin Pigmentation / Q000502:physiology; D014466:Ultraviolet Rays; D014820:Vitiligo / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH
keywords: alpha-melanocyte stimulating hormone; basal cell carcinoma; evolution; melanocortin 1 receptor; melanoma; pigmentation; red hair; skin type; squamous cell carcinoma; vitiligo