Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. Thody, A.J. et al. Phaeomelanin as well as eumelanin is present in human epidermis. J. invest Dermatol. 97, 340–344 (1991).

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Lu, D. et al. Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor. Nature 371, 799–802 (1994).

    Article  CAS  Google Scholar 

  6. Jackson, I.J. Colour-coded switches. Nature 362, 587–588 (1993).

    Article  CAS  Google Scholar 

  7. Jackson, I.J. More to colour than meets the eye. Curr. Biol. 3, 518–521 (1993).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. biol. Chem. 268, 8246–8250 (1993).

    CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  Google Scholar 

  12. Tsutsumi, M. et al. Cloning and functional expression of a mouse gonadotrophin releasing hormone receptor. Molec. Endocrinol. 6, 1163–1169 (1992).

    CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Eilberg, H. & Mohr, J. Major locus for red hair color linked to MNS blood groups on chromosome 4. Clin. Genet. 32, 125–128 (1987).

    Article  Google Scholar 

  15. Savov, A. et al. Double mutant alleles: are they rare? Hum. molec. Genet. 4, 1169–1171 (1995).

    Article  CAS  Google Scholar 

  16. 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).

    Google Scholar 

  17. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular cloning: A laboratory manual. (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  18. Russell, L.J. et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 9, 279–283 (1995).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Valverde, P., Healy, E., Jackson, I. et al. Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 11, 328–330 (1995).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing