Nature Genetics
11, 328 - 330 (1995)
doi:10.1038/ng1195-328
Variants of the melanocyte−stimulating hormone receptor gene are associated with red hair and fair skin in humansPaloma Valverde1, Eugene Healy1, Ian Jackson2, Jonathan L. Rees1
& Anthony J. Thody1
1Department of Dermatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
2MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK Correspondence should be addressed to A.J.T. Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeome-lanin and the black eumelanin, both of which are present in human skin1. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR2, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain 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 UVR1. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin3,4 and the product of the agouti locus which antagonises this action5. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogene-sis resulting in changes in coat colour6,7. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.
REFERENCES
- Thody, A.J. et al. Phaeomelanin as well as eumelanin is present in human epidermis. J. invest Dermatol. 97, 340−344 (1991).
- Ranadive, N.S., Shirwadkar, S., Persad, S. & Menon, I.A. Effects of melanin induced free radicals on the isolated rat peritoneal mast cells. J. invest. Dermatol. 86, 303−307 (1986).
- Burchill, S.A., Ito, S. & Thody, A.J. Effects of melanocyte stimulating hormone on tyrosinase expression and melanin synthesis in hair follicular melanocytes of the mouse. J. Endocrinol. 137, 189−195 (1993).
- Hunt, G., Kyne, S., Wakamatsu, K., Ito, S. & Thody, A.J. Nle4DPhe7a-MSH increases the eumelanin: phaeomelanin ratio in cultured human melanocytes. J. invest. Dermatol. 104, 83−85 (1995).
- Lu, D. et al. Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor. Nature 371, 799−802 (1994).
- Jackson, I.J. Colour-coded switches. Nature 362, 587−588 (1993).
- Jackson, I.J. More to colour than meets the eye. Curr. Biol. 3, 518−521 (1993).
- Mountjoy, K.G., Robbins, L.S., Mortrud, M.T. & Cone, R.D. The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248−1251 (1992).
- Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. biol. Chem. 268, 8246−8250 (1993).
- Fryxell, K.J. & Meyerowitz, E.M. An opsin that is only expressed in the R7 photoreceptor cell of Drosophila. EMBO J. 6, 443−451 (1987).
- Montell, C., Jones, K., Zuker, C. & Rubin, G. A second opsin gene expressed in the ultraviolet-sensitive R7 photoreceptor. J. Neurosci. 7, 1158−1166 (1987).
- Tsutsumi, M. et al. Cloning and functional expression of a mouse gonadotrophin releasing hormone receptor. Molec. Endocrinol. 6, 1163−1169 (1992).
- Robbins, L.S. et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827−834 (1993).
- Eilberg, H. & Mohr, J. Major locus for red hair color linked to MNS blood groups on chromosome 4. Clin. Genet. 32, 125−128 (1987).
- Savov, A. et al. Double mutant alleles: are they rare? Hum. molec. Genet. 4, 1169−1171 (1995).
- Fitzpatrick, T.B., Eisen, A.Z., Wolff, K., Freedberg, I.M. & Austen, K.F. in Dermatology in General Medicine. Third Edition. (McGraw-Hill, New York, 1987).
- Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular cloning: A laboratory manual. (Cold Spring Harbor Laboratory Press, New York, 1989).
- Russell, L.J. et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 9, 279−283 (1995).
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