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Human Molecular Genetics Advance Access originally published online on June 22, 2005
Human Molecular Genetics 2005 14(15):2145-2154; doi:10.1093/hmg/ddi219
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk

Kimberley A. Beaumont1, Richard A. Newton1, Darren J. Smit1, J. Helen Leonard2, Jennifer L. Stow1 and Richard A. Sturm1,*

1Melanogenix Group, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia and 2Queensland Radium Institute Research Unit, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia

* To whom correspondence should be addressed. Tel: +61 7 33462038; Fax: +61 7 33462101; Email: r.sturm{at}imb.uq.edu.au

Received April 15, 2005; Revised May 31, 2005; Accepted June 14, 2005

The human melanocortin-1 receptor gene (MC1R) encodes a G-protein coupled receptor that is primarily expressed on melanocytes, where it plays a key role in pigmentation regulation. Variant alleles are associated with red hair colour and fair skin, known as the RHC phenotype, as well as skin cancer risk. The R151C, R160W and D294H alleles, designated ‘R’, are strongly associated with the RHC phenotype and have been proposed to result in loss of function receptors due to impaired G-protein coupling. We recently provided evidence that the R151C and R160W variants can efficiently couple to G-proteins in response to {alpha}-melanocyte stimulating hormone. The possibility that altered cellular localization of the R151C and R160W variant receptors could underlie their association with RHC was therefore considered. Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors. In additional exogenous expression studies, the R variant D84E and the rare I155T variant, also demonstrated a significant reduction in plasma membrane receptor numbers. The V60L, V92M and R163Q weakly associated RHC alleles, designated ‘r’, were expressed with normal or intermediate cell surface receptor levels. These results indicate that reduced receptor coupling activity may not be the only contributing factor to the genetic association between the MC1R variants and the RHC phenotype, with MC1R polymorphisms now linked to a change in receptor localization.


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