Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles
Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles
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DOI：
10.1093/hmg/ddm177
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发表时间：
2007-09-15
影响因子：
3.5
通讯作者：
Sturm, Richard A.
中科院分区：
文献类型：
--
作者：
Beaumont, Kimberley A.;Shekar, Sri L.;Sturm, Richard A.
人黑皮质素-1受体（MC 1 R）是一种参与色素沉着调节的G蛋白偶联受体。几个MC 1 R变异等位基因与红头发，白皙皮肤和皮肤癌风险增加有关。我们对9种常见的MC 1 R变体进行了系统的功能分析，并将这些结果与每个变体等位基因与色素沉着表型的遗传关联强度相关联。体外表达研究显示，细胞表面表达减少的变体受体，包括V60 L、D84 E、R151 C、I155 T、R160 W和R163 Q，在cAMP偶联中显示出相应的损伤。R142 H和D294 H变体表现出正常的细胞表面表达，但功能反应降低，表明改变的G蛋白偶联可能是导致这种功能丧失的原因。V92 M变体cAMP活化等于或高于野生型MC 1 R。在共表达研究中，D84 E、R151 C、I155 T和R160 W变体显示出对野生型受体细胞表面表达的显性负效应，这反映在升高细胞内cAMP水平的能力降低。D294 H变体还表现出对野生型MC 1 R cAMP信号传导的显性负效应，但对野生型表面表达没有影响。重要的是，在体外受体的特点与皮肤和头发的颜色数据的个人纯合子和杂合子的MC 1 R变异等位基因的比较显示变异MC 1 R细胞表面表达，功能能力，显性负活性和它们对人类色素沉着的影响之间的平行关系。这些发现表明变异MC 1 R生化特性和色素沉着表型之间的第一个直接相关性。
The human melanocortin-1 receptor (MC1R) is a G-protein coupled receptor involved in the regulation of pigmentation. Several MC1R variant alleles are associated with red hair, fair skin and increased skin cancer risk. We have performed a systematic functional analysis of nine common MC1R variants and correlated these results with the strength of the genetic association of each variant allele with pigmentation phenotypes. In vitro expression studies revealed that variant receptors with reduced cell surface expression, including V60L, D84E, R151C, I155T, R160W and R163Q, showed a corresponding impairment in cAMP coupling. The R142H and D294H variants demonstrated normal cell surface expression, but had reduced functional responses, indicating that altered G-protein coupling may be responsible for this loss of function. The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R. In co-expression studies, the D84E, R151C, I155T and R160W variants showed a dominant negative effect on wild-type receptor cell surface expression, which was reflected in a decreased ability to elevate intracellular cAMP levels. The D294H variant also demonstrated a dominant negative effect on wild-type MC1R cAMP signalling, but had no effect on wild-type surface expression. Importantly, comparison of the in vitro receptor characteristics with skin and hair colour data of individuals both homozygous and heterozygous for MC1R variant allelles revealed parallels between variant MC1R cell surface expression, functional ability, dominant negative activity and their effects on human pigmentation. These findings show the first direct correlations between variant MC1R biochemical properties and pigmentation phenotype.