Red hair, skin pigmentation and the MC1R variants.

Just a collection of ginger-related articles .

Melanocortin 1 Receptor Variants in an Irish Population

Received 11 November 1997; Revised 25 February 1998; Accepted 13 March 1998.

The identification of an association between variants in the human melanocortin 1 receptor (MC1R) gene and red hair and fair skin, as well as the relation between variants of this gene and coat color in animals, suggests that the MC1R is an integral control point in the normal pigmentation phenotype. In order to further define the contribution of MC1R variants to pigmentation in a normal population, we have looked for alterations in this gene in series of individuals from a general Irish population, in whom there is a preponderance of individuals with fair skin type. Seventy-five per cent contained a variant in the MC1R gene, with 30% containing two variants. The Arg151Cys, Arg160Trp, and Asp294His variants were significantly associated with red hair (p = 0.0015, p < 0.001, and p < 0.005, respectively). Importantly, no individuals harboring two of these three variants did not have red hair, although some red-haired individuals only showed one alteration. The same three variants were also over-represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these associations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype. The Asp294His variant was similarly associated with red hair in a Dutch population, but was infrequent in red-headed subjects from Sweden. The Asp294His variant was also significantly associated with nonmelanoma skin cancer in a U.K. population. The results show that the Arg151Cys, Arg160Trp, and Asp294His variants are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red-haired component and in some cases fair skin type are inherited as a Mendelian recessive.


Effect of Val92Met and Arg163Gln variants of the MC1R gene on freckles and solar lentigines in Japanese.

Short Communication

Pigment Cell Research. 20(2):140-143, April 2007.
Motokawa, Tomonori 1,*; Kato, Tomomi 1; Hashimoto, Yuki 2; Katagiri, Takayuki 1

Summary: Melanocortin-1 receptor (MC1R) is a highly polymorphic gene. The variety of the variants is dependent on the ethnic background of the individual. In Caucasians, specific variants, such as Arg151Cys, Arg160Trp, and Asp294His, are strongly associated with red hair, skin cancer and pigmented lesions. In Asians, there is no report so far indicating an association such as that observed in Caucasians. Here, we performed an association study on melanogenic phenotypes in 245 Japanese individuals. We focused on freckles and solar lentigines as melanogenic phenotypes. The 92Met allele and the 163Arg allele were positively associated with freckles and severe solar lentigines; the 163Gln allele showed a negative association. Those subjects who were homozygous for both the 92Met and 163Arg alleles had a highly elevated risk of developing freckles (OR: 7.92; 95% CI: 1.52-39.6) and severe solar lentigines (OR: 4.08; 95% CI: 1.34-13.1). Our study is the first report to show a clear association of MC1R variants on melanogenic phenotypes in Asians and also indicates the importance of Arg163Gln. In vitro studies by other groups demonstrated that Val92Met impaired MC1R function but Arg163Gln did not. Based on these in vitro studies, we believe that the result we observed for Val92Met could be attributed to impaired MC1R function, while, for Arg163Gln, other factors, e.g. effect of other loci, need to be considered.

Copyright (C) 2007 Blackwell Publishing Ltd.


The melanocortin-1-receptor gene is the major freckle gene

Maarten Bastiaens, Jeanette ter Huurne, Nelleke Gruis, Wilma Bergman, Rudi Westendorp1, Bert-Jan Vermeer and Jan-Nico Bouwes Bavinck+

Department of Dermatology and 1Department of Clinical Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands

Received April 17, 2001; Revised and Accepted June 12, 2001.

Ephelides and solar lentigines are different types of pigmented skin lesions. Ephelides 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 non-melanoma skin cancer. Melanocortin-1-receptor (MC1R) gene variants are also associated with fair skin, red hair and melanoma and non-melanoma skin cancer. The purpose of this study was to investigate the relationship between MC1R gene variants, ephelides and solar lentigines. In a large case-control study, patients with melanoma and non-melanoma skin cancer and subjects without a history of skin cancer were studied. In all participants, the presence of ephelides in childhood and solar lentigines by physical examination was assessed according to strict definitions. The entire coding sequence of the MC1R gene was analyzed by single-strand conformation polymorphism analysis followed by sequence analyses. Carriers of one or two MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P < 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P < 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%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. 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 one MC1R gene variant, our data suggest that MC1R gene variants are necessary to develop ephelides. The results of the study also suggest that MC1R gene variants play a role, although less important, in the development of solar lentigines.


Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation

M. Cathy Scott1, Kazumasa Wakamatsu2, Shosuke Ito2, Ana Luisa Kadekaro1, Nobuhiko Kobayashi3, Joanna Groden4, Renny Kavanagh1, Takako Takakuwa5, Victoria Virador6, Vincent J. Hearing6 and Zalfa A. Abdel-Malek1,*

Accepted 6 March 2002

Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of -melanotropin (-melanocyte-stimulating hormone) to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to -melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to -melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eumelanin and pheomelanin contents were determined. Human melanocytes homozygous for Arg160Trp, heterozygous for Arg160Trp and Asp294His, or for Arg151Cys and Asp294His substitutions, but not melanocytes homozygous for Val92Met substitution, in the MC1R demonstrated a significantly reduced response to -melanotropin. Additionally, melanocytes with a non-functional MC1R demonstrated a pronounced increase in their sensitivity to the cytotoxic effect of UV radiation compared with melanocytes expressing functional MC1R. We conclude 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.


Evidence for Variable Selective Pressures at MC1R
References AbstractIt is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.

High polymorphism at the MC1R gene makes a major contribution to phenotypic diversity in Eurasian populations

Melanocortin-1 receptor (MC1R), the receptor for alpha-melanocyte stimulating hormone, is polymorphic and plays an important role in producing two types of melanin, pheomelanin (red) and eumelanin (black), which are present in human skin and hair. In this study we examined the distribution of MC1R gene polymorphisms in several Eurasian populations. A total of 2591 subjects from 49 populations were included in the present investigation. The subjects were not selected for skin and hair colour and were collected randomly. 5 variants of the MC1R gene (Val60Leu, Val92Met, Arg151Cys, Arg160Trp and Arg163Gln) were tested using ARMS-PCR. Arg151Cys and Arg160Trp alleles, which are common in individuals with red hair and fair skin, were found at highest frequencies in British (AF=0.128 and 0.069, respectively) and Orkadian populations (AF=0.106 and 0.099, respectively), with a decreasing gradient in the populations of European Russia to Central Asia. Previously reported to be common in European populations with light fair skin and light brown hair, allele Val60Leu was identified with high frequency in some populations of the Middle East, Europe and Caucasus. Central Asian populations showed middle range frequencies. The Val92Met variant was found to have an allele frequency from 0.194 to 0.01 in the middle meridian of Eurasia, with a maximum in Central and South East Asian populations. Our data suggest an increasing gradient of Arg163Gln frequency from Europe (0.039) to South East Asia (0.66). As anticipated, our data showed low frequencies of all investigated variants in the populations of South India with dark skin and dark hair. These results indicate that polymorphisms of the MC1R contribute to determining skin and hair colour is one of the significant factor in the phenotypic diversity found in different Eurasian populations and are consistent with the widely held assumption that genes influencing phenotypic variation in human skin and hair pigmentation are probably subject to selection associated with latitude and sunlight.


4 responses to “Red hair, skin pigmentation and the MC1R variants.

  1. Hi, do you have the date of origin for this MC1R gene? Or when it arose in humans?


  2. I think this MCR gene is present in human since the time of its creation.

  3. Would you recommend where regular could have their DNA analyzed?
    Thank you. I have throughly enjoyed your work

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