Two types of melanin, the red pheomelanin and the black eumelanin, are present in human skin. Valverde et al. (1995) noted that eumelanin is photoprotective, whereas pheomelanin may contribute to UV-induced skin damage because of its potential to ... Two types of melanin, the red pheomelanin and the black eumelanin, are present in human skin. Valverde et al. (1995) noted that eumelanin is photoprotective, whereas pheomelanin may contribute to UV-induced skin damage because of its potential to generate free radicals in response to ultraviolet radiation. Individuals with red hair have a predominance of pheomelanin in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from ultraviolet radiation. In mammals, the relative proportions of pheomelanin and eumelanin are regulated by melanocyte-stimulating hormone (see 176830), which acts via its receptor (MC1R) on melanocytes to increase the synthesis of eumelanin, and also via the product of the agouti locus (AGTI; 600201), which antagonizes this action.
Valverde et al. (1995) found variants of the melanocyte-stimulating hormone receptor gene (MC1R; 155555) associated with red hair and fair skin and poor tanning response. The MC1R gene is located on chromosome 16.
In a study ... Valverde et al. (1995) found variants of the melanocyte-stimulating hormone receptor gene (MC1R; 155555) associated with red hair and fair skin and poor tanning response. The MC1R gene is located on chromosome 16. In a study of MC1R variation in 174 individuals from 11 large kindreds with a preponderance of red hair, an additional 99 unrelated redheads, and 167 randomly ascertained Caucasians, Flanagan et al. (2000) determined that heterozygotes for 2 alleles, R151C and 537insC, have a significantly elevated risk of red hair. The authors observed that the shade of red hair frequently differed in heterozygotes from that in homozygotes or compound heterozygotes. The authors also presented evidence for a heterozygote effect on beard hair color, skin type, and freckling. Ephelides and solar lentigines are different types of pigmented skin lesions (Bastiaens et al., 2001). Ephelides (freckles) appear early in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a sign of photodamage. Both lesions are strong risk indicators for melanoma and nonmelanoma skin cancer. In a large case-control study, Bastiaens et al. (2001) studied patients with melanoma and nonmelanoma skin cancer and subjects without a history of skin cancer. Carriers of 1 or 2 MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P less than 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P less than 0.0001), respectively. These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The population attributable risk for ephelides to MC1R gene variants was 60%, and a dosage effect was found between the degree of ephelides and the number of MC1R gene variants. As nearly all individuals with ephelides were carriers of at least 1 MC1R gene variant, the authors proposed that MC1R gene variants may be necessary to develop ephelides, and may play a less important role in the development of solar lentigines. In Jamaica there are persons who self-identify as black who have auburn/reddish hair, freckles, and a 'rust-colored' complexion (sometimes called 'red Ibos'). McKenzie et al. (2003) examined MC1R sequence and hair melanins in 4 Jamaican 'redheads.' Sequencing of the MC1R gene revealed that all of the redheads were compound heterozygotes for variants that were either known to or predicted to disrupt MC1R function. The melanin values were within the range seen in white UK individuals of equivalent MC1R status, suggesting that even on a different genetic background MC1R variants exert a significant phenotypic effect. McKenzie et al. (2003) concluded that red hair in this group (with West African ancestry) can be accounted for in terms of mutation of MC1R. See also 266350. Sulem et al. (2007) stated that more than 30 nonsynonymous mutations have been described in populations of European ancestry that impair the function of the MC1R product, leading to generation of melanosomes that contain red-yellow pheomelanin rather than brown-black eumelanin and resulting in such pigmentation traits as red and blond hair, freckles, fair skin, and sensitivity to ultraviolet radiation. Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling. The most closely associated SNPs from 6 regions were then tested for replication in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. Sulem et al. (2007) detected a 1-Mb region of strong linkage spanning 38 SNPs and containing the MC1R gene that was associated with red hair, skin sensitivity to sun, and freckles. SNPs within the region also showed a trend towards association with blond hair. The association signal was due to the previously reported SNPs dbSNP rs1805007 (R151C; 155555.0004) and dbSNP rs1805008 (R160W; 155555.0005). Analysis of allele frequencies suggested that both mutated alleles may have been at least weakly affected by recent positive selection.