Functional Analysis LRP6 Novel Mutations in Patients with Coronary Artery Disease
Functional Analysis LRP6 Novel Mutations in Patients with Coronary Artery Disease
复制标题
冠状动脉疾病患者 LRP6 新突变的功能分析
DOI：
10.1371/journal.pone.0084345
复制
发表时间：
2014-01-10
期刊：
影响因子：
3.7
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Xu, Yujun;Gong, Wei;Wang, Dao Wen
背景冠状动脉疾病（CAD）的遗传结构仍有待确定。由于低密度脂蛋白受体相关蛋白6（LRP 6）基因在Wnt信号转导中起关键作用，而Wnt信号转导对血管发育和内皮特化非常重要，因此我们对其进行了重测序以寻找CAD患者中的突变。方法对380例早发冠心病患者和380例正常对照者的LRP 6基因全部外显子和启动子区进行序列测定。结果共检测到5种患者特异性突变，包括K82N（2例）、S488Y（1例）、P1066T（2例）、P1206H（2例）和I1264V（1例）。对患者特异性突变的体外功能分析表明，这些突变导致转运至细胞膜的蛋白水平和下游Wnt信号活性显著降低。此外，我们发现LRP 6新突变减弱人脐静脉内皮细胞（HUVEC）的增殖和迁移相比，野生型（WT）LRP 6。结论这些功能缺失突变体可能与冠心病的易感性有关，Wnt信号激活缺陷可能是冠心病发病的重要因素。
Background Genetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients. Methods We systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese. Results In total, we identified 5 patient-specific mutations including K82N (two patients), S488Y (one patient), P1066T (two patients), P1206H (two patients) and I1264V (one patient) All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs) when compared with wild type (WT) LRP6. Conclusion Our results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD.