Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms
Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms
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DOI：
10.1093/hmg/ddq005
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Schoenwolf, Gary C.
中科院分区：
文献类型：
--
作者：
Bleyl, Steven B.;Saijoh, Yukio;Schoenwolf, Gary C.
完全性肺静脉回流异常（TAPVR）是一种通过复杂的遗传和/或环境因素遗传的先天性心脏病。我们报告了在TAPVR患者中扩展的TAPVR激酶和突变分析的详细映射，这些TAPVR患者涉及PDGFRA基因在TAPVR的发展中。在小鼠和鸡胚中对Pdgfra受体及其配体Pdgf-a的基因表达研究显示与肺静脉（PV）发育中的作用一致的时间和空间模式。我们使用鸡卵内功能阻断试验和小鼠条件性敲除方法来敲除PV形成期间发育中静脉极中的Pdgfra表达。我们观察到，PDGFRA功能的丧失在两种生物体中导致TAPVR具有低转化率（类似于7%），这让人想起在我们的人类TAPVR激酶中观察到的情况。中间流入道异常发生在较高比例的胚胎（类似于30%），表明TAPVR发生在一系列缺陷的一端。我们发现，在鸡和小鼠中观察到的异常肺静脉连接与在京都人类胚胎收集的异常早期胚胎中发现的TAPVR高度相似。尽管正常静脉极和PV的胚胎学正在被理解，但对TAPVR的胚胎发生或分子发病机制知之甚少。这些TAPVR模型为PV缺陷的发病机制提供了重要的见解。总之，这些来自人类遗传学和动物模型的数据支持PDGF信号在正常PV发育和TAPVR发病机制中的作用。
Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect inherited via complex genetic and/or environmental factors. We report detailed mapping in extended TAPVR kindreds and mutation analysis in TAPVR patients that implicate the PDGFRA gene in the development of TAPVR. Gene expression studies in mouse and chick embryos for both the Pdgfra receptor and its ligand Pdgf-a show temporal and spatial patterns consistent with a role in pulmonary vein (PV) development. We used an in ovo function blocking assay in chick and a conditional knockout approach in mouse to knock down Pdgfra expression in the developing venous pole during the period of PV formation. We observed that loss of PDGFRA function in both organisms causes TAPVR with low penetrance (similar to 7%) reminiscent of that observed in our human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (similar to 30%), suggesting that TAPVR occurs at one end of a spectrum of defects. We show that the anomalous pulmonary venous connection seen in chick and mouse is highly similar to TAPVR discovered in an abnormal early stage embryo from the Kyoto human embryo collection. Whereas the embryology of the normal venous pole and PV is becoming understood, little is known about the embryogenesis or molecular pathogenesis of TAPVR. These models of TAPVR provide important insight into the pathogenesis of PV defects. Taken together, these data from human genetics and animal models support a role for PDGF-signaling in normal PV development, and in the pathogenesis of TAPVR.