Skip to main content
SpringerLink
Log in

Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Human melanocortin 1 receptor (MC1R) is a seven transmembrane G-coupled protein receptor that upregulates the cAMP pathway. Several functional variants of MC1R that show an impaired ability to activate the cAMP pathway are strongly associated with fair skin and red hair in Europeans and European descendants. The sequence variations of the MC1R gene were repeatedly investigated against worldwide populations; however, there was no evidence that functional variant of MC1R exists in non-European descendants. We report the presence of novel functional variants of MC1R with Asian origins. Three novel variants of MC1R, Phe147Δ, Thr157Ile, and Pro159Thr, were identified in our screening for the sequence variations of the MC1R gene against 995 individuals from 30 Asian and Oceanian populations; there was a single case for the Pro159Thr variant allele and two instances of Phe147Δ and Thr157Ile variant alleles. Our pharmacological assay revealed that Phe147Δ, Thr157Ile, and Pro159Thr variant showed similar or more dramatically impaired activities in comparison with Arg151Cys, which is a major functional variant of MC1R in Europeans. These functional variant alleles were geographically localized in relatively high latitudes, which suggest that the adaptation to ambient UV light intensity may play an important role in shaping the geographical distribution of MC1R alleles in Asia and Oceania.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Akey JM, Wang H, Xiong M, Wu H, Liu W, Shriver MD, Jin L (2001) Interaction between the melanocortin-1 receptor and P genes contributes to inter-individual variation in skin pigmentation phenotypes in a Tibetan population. Hum Genet 108:516–520

    Article  PubMed  CAS  Google Scholar 

  • Bastiaens M, ter Huurne J, Gruis N, Bergman W, Westendorp R, Vermeer BJ, Bouwes Bavinck JN (2001) The melanocortin-1-receptor gene is the major freckle gene. Hum Mol Genet 10:1701–1708

    Article  PubMed  CAS  Google Scholar 

  • Beaumont KA, Newton RA, Smit DJ, Leonard JH, Stow JL, Sturm RA (2005) Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet 14:2145–2154

    Article  PubMed  CAS  Google Scholar 

  • Bellwood P (1996) Early agriculture and the dispersal of the southern Mongoloids. In: Akazawa T, Szathmary EJE (eds) Prehistoric mongoloid dispersals. Oxford University Press, New York, pp 287–302

    Google Scholar 

  • Bonilla C, Boxill LA, Donald SA, Williams T, Sylvester N, Parra EJ, Dios S, Norton HL, Shriver MD, Kittles RA (2005) The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans. Hum Genet 116:402–406

    Article  PubMed  CAS  Google Scholar 

  • Box NF, Wyeth JR, O’Gorman LE, Martin NG, Sturm RA (1997) Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet 6:1891–1897

    Article  PubMed  CAS  Google Scholar 

  • Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, Hayward NK, Martin NG, Sturm RA (2004) Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum Mol Gene 13:447–461

    Article  CAS  Google Scholar 

  • Excoffier L (2002) Human demographic history: refining the recent African origin model. Curr Opin Genet Dev 12:675–682

    Article  PubMed  CAS  Google Scholar 

  • Fargnoli MC, Chimenti S, Keller G, Hofler H, Peris K (2003) Identification of four novel melanocortin 1 receptor (MC1R) gene variants in a Mediterranean population. Hum Mutat 21:655

    Article  PubMed  CAS  Google Scholar 

  • Flanagan N, Healy E, Ray A, Philips S, Todd C, Jackson IJ, Birch-Machin MA, Rees JL (2000) Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Hum Mol Genet 9:2531–2537

    Article  PubMed  CAS  Google Scholar 

  • Frandberg PA, Doufexis M, Kapas S, Chhajlani V (1998) Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem Biophys Res Commun 245:490–492

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C (2005) Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res 18:393–410

    PubMed  CAS  Google Scholar 

  • Graf J, Hodgson R, van Daal A (2005) Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum Mutat 25:278–284

    Article  PubMed  CAS  Google Scholar 

  • Harding RM, Fullerton SM, Griffiths RC, Bond J, Cox MJ, Schneider JA, Moulin DS, Clegg JB (1997) Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet 60:772–789

    PubMed  CAS  Google Scholar 

  • Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, Rees JL (2000) Evidence for variable selective pressures at MC1R. Am J Hum Genet 66:1351–1361

    Article  PubMed  CAS  Google Scholar 

  • Healy E, Flannagan N, Ray A, Todd C, Jackson IJ, Matthews JN, Birch-Machin MA, Rees JL (2000) Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair. Lancet 25:1072–1073

    Article  Google Scholar 

  • Healy E, Jordan SA, Budd PS, Suffolk R, Rees JL, Jackson IJ (2001) Functional variation of MC1R alleles from red-haired individuals. Hum Mol Genet 10:2397–2402

    Article  PubMed  CAS  Google Scholar 

  • Hearing VJ (1999) Biochemical control of melanogenesis and melanosomal organization. J Investig Dermatol Symp Proc 4:24–28

    Article  PubMed  CAS  Google Scholar 

  • Hunt G, Kyne S, Wakamatsu K, Ito S, Thody AJ (1995) Nle4DPhe7 alpha-melanocyte-stimulating hormone increases the eumelanin:phaeomelanin ratio in cultured human melanocytes. J Invest Dermatol 104:83–85

    Article  PubMed  CAS  Google Scholar 

  • Ito S, IFPCS (2003) The IFPCS presidential lecture: a chemist’s view of melanogenesis. Pigment Cell Res 16:230–236

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Cervantes C, Olivares C, Gonzalez P, Morandini R, Ghanem G, Garcia-Borron JC (2001) The Pro162 variant is a loss-of-function mutation of the human melanocortin 1 receptor gene. J Invest Dermatol 117:156–158

    Article  PubMed  CAS  Google Scholar 

  • John PR, Makova K, Li WH, Jenkins T, Ramsay M (2003) DNA polymorphism and selection at the melanocortin-1 receptor gene in normally pigmented southern African individuals. Ann NY Acad Sci 994:299–306

    Article  PubMed  CAS  Google Scholar 

  • Kanetsky PA, Swoyer J, Panossian S, Holmes R, Guerry D, Rebbeck TR (2002) A polymorphism in the agouti signaling protein gene is associated with human pigmentation. Am J Hum Genet 70:770–775

    Article  PubMed  CAS  Google Scholar 

  • Kanetsky PA, Ge F, Najarian D, Swoyer J, Panossian S, Schuchter L, Holmes R, Guerry D, Rebbeck TR (2004) Assessment of polymorphic variants in the melanocortin-1 receptor gene with cutaneous pigmentation using an evolutionary approach. Cancer Epidemiol Biomarkers Prev 13:808–819

    PubMed  CAS  Google Scholar 

  • Makova K, Norton H (2005) Worldwide polymorphisms at the MC1R locus and normal pigmentation variation in humans. Peptides 26:1901–1908

    Article  PubMed  CAS  Google Scholar 

  • McKenzie CA, Harding RM, Tomlinson JB, Ray AJ, Wakamatsu K, Rees JL (2003) Phenotypic expression of melanocortin-1 receptor mutations in Black Jamaicans. J Invest Dermatol 121:207–208

    Article  PubMed  CAS  Google Scholar 

  • Motokawa T, Kato T, Hongo M, Ito M, Takimoto H, Katagiri T (2006) Characteristic MC1R polymorphism in the Japanese population. J Dermatol Sci 41:143–145

    Article  PubMed  CAS  Google Scholar 

  • Na GY, Lee KH, Kim MK, Lee SJ, Kim do W, Kim JC (2003) Polymorphisms in the melanocortin-1 receptor (MC1R) and agouti signaling protein (ASIP) genes in Korean vitiligo patients. Pigment Cell Res 16:383–387

    Article  PubMed  CAS  Google Scholar 

  • Nakayama K, Fukamachi S, Kimura H, Koda Y, Soemantri A, Ishida T (2002) Distinctive distribution of AIM1 polymorphism among major human populations with different skin color. J Hum Genet 47:92–94

    Article  PubMed  CAS  Google Scholar 

  • Naysmith L, Waterston K, Ha T, Flanagan N, Bisset Y, Ray A, Wakamatsu K, Ito S, Rees JL (2004) Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status. J Invest Dermatol 122:423–428

    Article  PubMed  CAS  Google Scholar 

  • Newton RA, Smit SE, Barnes CC, Pedley J, Parsons PG, Sturm RA (2005) Activation of the cAMP pathway by variant human MC1R alleles expressed in HEK and in melanoma cells. Peptides 26:1818–1824

    Article  PubMed  CAS  Google Scholar 

  • Palmer JS, Duffy DL, Box NF, Aitken JF, O’Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA (2000) Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 66:176–186

    Article  PubMed  CAS  Google Scholar 

  • Peng S, Lu XM, Luo HR, Xiang-Yu JG, Zhang YP (2001) Melanocortin-1 receptor gene variants in four Chinese ethnic populations. Cell Res 11:81–84

    Article  PubMed  CAS  Google Scholar 

  • Rana BK, Hewett-Emmett D, Jin L, Chang BH, Sambuughin N, Lin M, Watkins S, Bamshad M, Jorde LB, Ramsay M, Jenkins T, Li WH (1999) High polymorphism at the human melanocortin 1 receptor locus. Genetics 151:1547–1557

    PubMed  CAS  Google Scholar 

  • Rees JL (2004) The genetics of sun sensitivity in humans. Am J Hum Genet 75:739–751

    Article  PubMed  CAS  Google Scholar 

  • Ringholm A, Klovins J, Rudzish R, Phillips S, Rees JL, Schioth HB (2004) Pharmacological characterization of loss of function mutations of the human melanocortin 1 receptor that are associated with red hair. J Invest Dermatol 123:917–923

    Article  PubMed  CAS  Google Scholar 

  • Schiöth HB, Phillips SR, Rudzish R, Birch-Machin MA, Wikberg JE, Rees JL (1999) Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair. Biochem Biophys Res Commun 260:488–491

    Article  PubMed  Google Scholar 

  • Scott MC, Wakamatsu K, Ito S, Kadekaro AL, Kobayashi N, Groden J, Kavanagh R, Takakuwa T, Virador V, Hearing VJ, Abdel-Malek ZA (2002) Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. J Cell Sci 115:2349–2355

    PubMed  CAS  Google Scholar 

  • Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, Pfaff C, Jones C, Massac A, Cameron N, Baron A, Jackson T, Argyropoulos G, Jin L, Hoggart CJ, McKeigue PM, Kittles RA (2003) Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112:387–399

    PubMed  Google Scholar 

  • Smith R, Healy E, Siddiqui S, Flanagan N, Steijlen PM, Rosdahl I, Jacques JP, Rogers S, Turner R, Jackson IJ, Birch-Machin MA, Rees JL (1998) Melanocortin 1 receptor variants in an Irish population. J Invest Dermatol 111:119–122

    Article  PubMed  CAS  Google Scholar 

  • Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA (1996) Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 137:1627–1633

    Article  PubMed  CAS  Google Scholar 

  • Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595

    PubMed  CAS  Google Scholar 

  • Valverde P, Healy E, Jackson I, Rees JL, Thody AJ (1995) Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 11:328–330

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Hirayasu K, Ishizawa M, Kobayashi Y (1994) Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. Nucleic Acids Res 22:1774–1775

    Article  PubMed  CAS  Google Scholar 

  • Wong TH, Rees JL (2005) The relation between melanocortin 1 receptor (MC1R) variation and the generation of phenotypic diversity in the cutaneous response to ultraviolet radiation. Peptides 26:1965–1971

    Article  PubMed  CAS  Google Scholar 

  • Yao YG, Lu XM, Luo HR, Li WH, Zhang YP (2000) Gene admixture in the Silk Road region of China: evidence from mtDNA and melanocortin 1 receptor polymorphism. Genes Genet Syst 75:173–178

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This paper is dedicated to Drs Satoshi Horai and Surin Pookajorn. We are grateful to Drs M. Hirai and P.N. Tongol-Rivera for sharing DNA samples. This study was partly supported by the Japan Society for Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology, Japan and University of Tokyo. This study constitutes a part of the doctoral thesis of K.N. submitted to The University of Tokyo.

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 1130033, Tokyo, Japan

    Kazuhiro Nakayama, Shinji Harihara & Takafumi Ishida

  2. Department of Pediatrics, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

    Augustinus Soemantri

  3. Institute of Genetics, Chinese Academy of Science, Beijing, China

    Feng Jin

  4. Institute of Biological Science, Mongolian Academy of Science, Ulan-Baatar, Mongolia

    Bumbein Dashnyam

  5. National Institute for Environmental Studies, Tsukuba-City, Ibaraki, Japan

    Ryutaro Ohtsuka

  6. Srinakarinwirot University, Bangkok, Thailand

    Phaibool Duanchang

  7. International Medical University, Kuala Lumpur, Malaysia

    Mohd Nizam Isa

  8. Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Wannapa Settheetham-Ishida

Authors
  1. Kazuhiro Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Augustinus Soemantri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bumbein Dashnyam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryutaro Ohtsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Phaibool Duanchang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohd Nizam Isa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wannapa Settheetham-Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shinji Harihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takafumi Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takafumi Ishida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakayama, K., Soemantri, A., Jin, F. et al. Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians. Hum Genet 119, 322–330 (2006). https://doi.org/10.1007/s00439-006-0141-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0141-1

Keywords

Search

Navigation