Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease.
Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease.
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DOI：
10.3390/ijms17071173
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发表时间：
2016-07-22
影响因子：
5.6
通讯作者：
Tian XL
中科院分区：
文献类型：
--
作者：
Guo J;Li Y;Ren YH;Sun Z;Dong J;Yan H;Xu Y;Wang DW;Zheng GY;Du J;Tian XL
在冠心病（CAD）家族中报告了低密度脂蛋白（LDL）受体相关蛋白6（LRP 6）和肌细胞增强因子2A（MEF 2A）基因突变。我们打算确定这些基因的突变谱之间的高血脂和血脂正常的CAD家庭。从19个高脂血症和21个正常脂血症中国家系中招募40名早发CAD先证者。我们对LRP 6和MEF 2A的所有外显子和内含子-外显子边界进行了测序，并在一名血脂正常的CAD先证者的LRP 6中发现了一种新的杂合变体。该变异导致外显子6中进化保守结构域YWTD中组氨酸被酪氨酸（Y 418 H）取代，并且在1025名无关健康个体中未发现。在受累家族中与CAD共分离，LRP 6 Y 418 H显著削弱了Wnt 3a相关信号通路，抑制了内皮细胞增殖和迁移，并降低了抗凋亡能力。然而，它对低密度脂蛋白胆固醇摄取没有影响。因此，LRP 6中的突变Y 418 H可能通过损害内皮细胞功能和削弱Wnt 3a信号传导途径而促成血脂正常的家族性CAD。
Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway.