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Human Molecular Genetics Advance Access published online on June 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi219
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received April 15, 2005
Revised May 31, 2005
Accepted June 14, 2005

Article

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

Kimberley A. Beaumont 1, Richard A. Newton 1, Darren J. Smit 1, J. Helen Leonard 2, Jennifer L. Stow 1, and Richard A. Sturm 3*

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

* To whom correspondence should be addressed.
Richard A. Sturm, E-mail: R.Sturm{at}imb.uq.edu.au


  Abstract

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 localisation 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 localisation 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 MC1R variants and the RHC phenotype, with MC1R polymorphisms now linked to a change in receptor localisation.


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