Beaumont Kimberley A, Newton Richard A, Smit Darren J, Leonard J Helen, Stow Jennifer L, Sturm Richard A
Melanogenix Group, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Hum Mol Genet. 2005 Aug 1;14(15):2145-54. doi: 10.1093/hmg/ddi219. Epub 2005 Jun 22.
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.
人类黑皮质素-1受体基因（MC1R）编码一种G蛋白偶联受体，该受体主要在黑素细胞上表达，在色素沉着调节中起关键作用。变异等位基因与红头发和白皙皮肤相关，即所谓的RHC表型，同时也与皮肤癌风险有关。被称为“R”的R151C、R160W和D294H等位基因与RHC表型密切相关，有人提出这些等位基因会因G蛋白偶联受损而导致功能丧失的受体。我们最近提供的证据表明，R151C和R160W变体能够响应α-黑素细胞刺激激素有效地与G蛋白偶联。因此，人们考虑了R151C和R160W变体受体细胞定位改变可能是其与RHC相关的原因。通过免疫荧光和配体结合研究，我们发现外源性或内源性表达MC1R的黑素细胞显示野生型和D294H等位基因有很强的表面定位，但R151C和R160W受体的细胞表面表达明显减少。在额外的外源性表达研究中，R变体D84E和罕见的I155T变体也显示质膜受体数量显著减少。与RHC弱相关的等位基因V60L、V92M和R163Q，即“r”，其细胞表面受体水平正常或中等。这些结果表明，受体偶联活性降低可能不是MC1R变体与RHC表型之间遗传关联的唯一因素，现在MC1R多态性与受体定位的改变有关。
