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Single nucleotide polymorphisms (<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s, also termed variants) in <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> frequently cause red hair, fair skin and are associated with melanoma and keratinocyte\u2010derived skin cancer development. Activation of wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R in skin assists cutaneous photoprotection whereas reduced <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R signalling, seen with <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> variants, impairs ultraviolet radiation (<jats:styled-content style=\"fixed-case\">UVR<\/jats:styled-content>)\u2010protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> variants may have related to improved cutaneous vitamin D synthesis and higher birthweight reported with certain <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> variants. Reduced photoprotection secondary to <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> dysfunction involves pigmentary and non\u2010pigmentary mechanisms (reduced <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> 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 <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> genotype and vitiligo, with preliminary evidence that a <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R agonist, [Nle4\u2010D\u2010Phe7]\u2010alpha\u2010<jats:styled-content style=\"fixed-case\">MSH<\/jats:styled-content>, in combination with <jats:styled-content style=\"fixed-case\">UVB<\/jats:styled-content>, assists repigmentation. Future development of compounds to correct defective <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R responses secondary to <jats:italic><jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1R<\/jats:italic> variants could result in photoprotective benefits for fair\u2010skinned individuals and reduce their skin cancer risk.<\/jats:p>","DOI":"10.1111\/exd.12540","type":"journal-article","created":{"date-parts":[[2014,9,15]],"date-time":"2014-09-15T11:41:09Z","timestamp":1410781269000},"page":"5-9","source":"Crossref","is-referenced-by-count":20,"title":["Variants of the melanocortin\u20101 receptor: do they matter clinically?"],"prefix":"10.1111","volume":"24","author":[{"given":"Ciara","family":"Haddadeen","sequence":"first","affiliation":[{"name":"Dermatopharmacology Sir Henry Wellcome Laboratories Faculty of Medicine University of Southampton Southampton UK"},{"name":"Dermatology University Hospital Southampton NHS Foundation Trust Southampton 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