Alternative titles; symbols
Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q24.3 | [Skin/hair/eye pigmentation 2, blond hair/fair skin] | 266300 | Autosomal recessive | 3 | MC1R | 155555 |
| 16q24.3 | [Skin/hair/eye pigmentation 2, red hair/fair skin] | 266300 | Autosomal recessive | 3 | MC1R | 155555 |
| 16q24.3 | {UV-induced skin damage} | 266300 | Autosomal recessive | 3 | MC1R | 155555 |
A number sign (#) is used with this entry because of evidence that variation in the MC1R gene (155555) is involved in the determination of red hair, fair skin, and freckles.
For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see 227220.
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.
Neel (1943) was of the opinion that red hair is recessive, with occasional penetrance in heterozygotes and hypostasis to factors determining black or brown hair. Reed (1952) questioned whether red hair 'segregates' when macroscopic methods for scoring subjects are used. Rife (1967) concluded that the proportion of red-haired offspring in families in which one or both parents are red-haired is too high to support the hypothesis that red hair is inherited as a simple recessive. The family data and gene frequency analysis suggested to him that the presence of red pigment in the hair is dominant to its absence and is hypostatic to brown or black.
Spritz (1995) pointed out puzzling features: one might expect mutations associated with red hair to be recessive; most of the red-head and fair-skinned individuals in their study were either heterozygous or had no identifiable mutations. In other species, amino acid substitutions within or adjacent to the second transmembrane domain of the MSHR polypeptide constitutively activate the corresponding receptors, resulting in dominant alleles. Alternatively, alleles that are associated with red coat color in Norwegian red cattle (Klungland et al., 1995) and in the red guinea pig are recessive and contain null mutations.
In Copenhagen, Hauge and Helweg-Larsen (1954) found the prevalence of 'strikingly red hair' to be 1.9%.
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 rs1805007 (R151C; 155555.0004) and rs1805008 (R160W; 155555.0005). Analysis of allele frequencies suggested that both mutated alleles may have been at least weakly affected by recent positive selection.
Joerg et al. (1996) demonstrated that red coat color in Holstein cattle is associated with a deletion in the MSHR gene. Chestnut (red) coat color in horses was shown by Johansson et al. (1994) to cosegregate with polymorphism at the MSHR locus. Marklund et al. (1996) demonstrated that polymorphism consists of a single missense mutation, ser83phe, in the MC1R allele associated with the chestnut color. The substitution occurs in the second transmembrane region, which apparently plays a key role in the molecule since substitutions associated with coat color variance in mice and cattle as well as red hair and fair skin in humans are found in this part of the molecule.
An MC1R arg306-to-ter (R306X) mutation was shown to cause a completely red or yellow coat color in certain dog breeds such as Irish setters, yellow Labrador retrievers, and golden retrievers (Newton et al., 2000; Everts et al., 2000). Black mask is a characteristic pattern in which red, yellow, tan, fawn, or brindle dogs exhibit a melanistic muzzle which may extend up onto the ears. Melanistic mask is inherited in several dog breeds as an autosomal dominant trait, and appears to be a fixed trait in a few breeds. Schmutz et al. (2003) examined the amino acid sequence of the MC1R gene in 17 dogs with melanistic masks from 7 breeds, 19 dogs without melanistic masks, and 7 dogs in which their coat color made the mask difficult to distinguish. All dogs with a melanistic mask had at least one copy of a valine substitution for methionine at amino acid 264 (M264V) and none was homozygous for the R306X mutation.
Mitra et al. (2012) introduced a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene, Mc1r(e/e), which results in a phenotype analogous to red hair/fair skin humans. The authors observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet radiation-independent carcinogenesis, Mitra et al. (2012) introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. Mitra et al. (2012) concluded that these data suggested that the pheomelanin pigment pathway produces ultraviolet radiation-independent carcinogenic contributions to melanogenesis by a mechanism of oxidative damage. The authors further concluded that although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.
Gedde-Dahl (1984) suggested that red hair may be in the same linkage group as epidermolysis bullosa progressiva and hypoacusis (226500). Koletzko et al. (1987) suggested that red hair is linked to ataxia-deafness-retardation syndrome (208850).
Eiberg and Mohr (1987) reviewed Danish material of normal families that had been tested previously for 65 marker systems. Red hair (RHC) was found in 4.85% of parents. Scoring RHC for linkage purposes as an autosomal dominant versus blond and as hypostatic to dark hair gave a maximum lod score of 5.50 at theta = 0.05 in males and 0.24 in females for linkage to MNS (111300).
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Everts, R. E., Rothuizen, J., van Oost, B. A. Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and golden retrievers with yellow coat colour. Animal Genet. 31: 194-199, 2000. [PubMed: 10895310] [Full Text: https://doi.org/10.1046/j.1365-2052.2000.00639.x]
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Hauge, M., Helweg-Larsen, H. F. Studies on linkage in man: red hair versus blood groups, PTC and eye colour. Ann. Eugen. 18: 175-182, 1954. [PubMed: 13125201] [Full Text: https://doi.org/10.1111/j.1469-1809.1952.tb02510.x]
Joerg, H., Fries, H. R., Meijerink, E., Stranzinger, G. F. Red coat color in Holstein cattle is associated with a deletion in the MSHR gene. Mammalian Genome 7: 317-318, 1996. [PubMed: 8661706] [Full Text: https://doi.org/10.1007/s003359900090]
Johansson, M., Marklund, L., Sandberg, K., Andersson, L. Cosegregation between the chestnut coat colour in horses and polymorphisms at the melanocyte stimulating hormone (MSH) receptor locus. (Abstract) Animal Genet. 25 (Suppl. 2): 35 only, 1994.
Klungland, H., Vage, D. I., Gomez-Raya, L., Adalsteinsson, S., Lien, S. The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination. Mammalian Genome 6: 636-639, 1995. [PubMed: 8535072] [Full Text: https://doi.org/10.1007/BF00352371]
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McKenzie, C. A., Harding, R. M., Tomlinson, J. B., Ray, A. J., Wakamatsu, K., Rees, J. L. Phenotypic expression of melanocortin-1 receptor mutations in black Jamaicans. J. Invest. Derm. 121: 207-208, 2003. [PubMed: 12839583] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12314.x]
Mitra, D., Luo, X., Morgan, A., Wang, J., Hoang, M. P., Lo, J., Guerrero, C. R., Lennerz, J. K., Mihm, M. C., Wargo, J. A., Robinson, K. C., Devi, S. P., Vanover, J. C., D'Orazio, J. A., McMahon, M., Bosenberg, M. W., Haigis, K. M., Haber, D. A., Wang, Y., Fisher, D. E. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491: 449-453, 2012. [PubMed: 23123854] [Full Text: https://doi.org/10.1038/nature11624]
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