LRP6 mutation in a family with early coronary disease and metabolic risk factors
LRP6 mutation in a family with early coronary disease and metabolic risk factors
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DOI：
10.1126/science.1136370
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发表时间：
2007-03-02
期刊：
影响因子：
56.9
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Mani, Arya;Radhakrishnan, Jayaram;Lifton, Richard P.
冠状动脉疾病(CAD)是全球主要的死亡原因，通常由一系列称为代谢综合征的危险因素引起。我们描述了一个常染色体显性遗传的早期冠心病、代谢综合征(高脂血症、高血压和糖尿病)和骨质疏松症的特征。这些性状显示与染色体12p的一小段存在遗传连锁，我们在其中发现了LRP6的错义突变，LRP6编码Wnt信号通路中的一个辅助受体。该突变在表皮生长因子样域的一个高度保守的残基上用半胱氨酸取代精氨酸，在体外削弱了Wnt信号。这些结果将Wnt信号中的单个基因缺陷与冠心病和多种心血管危险因素联系起来。
Coronary artery disease ( CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.