Congenital heart defects affect ∼2% of live births and often involve malformations of the semilunar (aortic and pulmonic) valves. We previously reported a highly penetrant GATA4 p.Gly296Ser mutation in familial, congenital atrial septal defects and pulmonic valve stenosis and showed that mice harboring the orthologous G295S disease-causing mutation display not only atrial septal defects, but also semilunar valve stenosis. Here, we aimed to characterize the role of Gata4 in semilunar valve development and stenosis using the Gata4^G295Ski/wt mouse model. GATA4 is highly expressed in developing valve endothelial and interstitial cells. Echocardiographic examination of Gata4^G295Ski/wt mice at 2 months and 1 year of age identified functional semilunar valve stenosis predominantly affecting the aortic valve with distal leaflet thickening and severe extracellular matrix (ECM) disorganization. Examination of the aortic valve at earlier postnatal timepoints demonstrated similar ECM abnormalities consistent with congenital disease. Analysis at embryonic timepoints showed a reduction in aortic valve cushion volume at embryonic day (E)13.5, predominantly affecting the non-coronary cusp (NCC). Although total cusp volume recovered by E15.5, the NCC cusp remained statistically smaller. As endothelial to mesenchymal transition (EMT)-derived cells contribute significantly to the NCC, we performed proximal outflow tract cushion explant assays and found EMT deficits in Gata4^G295Ski/wt embryos along with deficits in cell proliferation. RNA-seq analysis of E15.5 outflow tracts of mutant embryos suggested a disease state and identified changes in genes involved in ECM and cell migration as well as dysregulation of Wnt signaling. By utilizing a mouse model harboring a human disease-causing mutation, we demonstrate a novel role for GATA4 in congenital semilunar valve stenosis.This article has an associated First Person interview with the joint first authors of the paper.

中文翻译：

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在具有先天性心脏病相关的GATA4突变的小鼠中鉴定出半月瓣狭窄的发展起源。

先天性心脏缺陷影响约2％的活产婴儿，并且经常涉及半月形（主动脉和肺动脉）瓣膜畸形。我们先前报道了家族性，先天性房间隔缺损和肺动脉瓣狭窄中高度渗透性的GATA4 p.Gly296Ser突变，并表明携带直系同源G295S致病突变的小鼠不仅表现出房间隔缺损，而且还表现出半月瓣狭窄。在这里，我们旨在使用Gata4 ^{G295Ski / wt}小鼠模型表征Gata4在半月瓣发育和狭窄中的作用。GATA4在发育中的瓣膜内皮细胞和间质细胞中高度表达。Gata4 ^{G295Ski / wt的}超声心动图检查2月龄和1岁大的小鼠发现功能性半月瓣狭窄主要影响主动脉瓣，并伴有远端小叶增厚和严重的细胞外基质（ECM）紊乱。在出生后较早的时间检查主动脉瓣显示出与先天性疾病相一致的类似ECM异常。胚胎时间点的分析显示，在胚胎天（E）13.5，主动脉瓣垫体积减少，主要影响了非冠状动脉尖（NCC）。尽管E15.5恢复了总的尖瓣体积，但NCC尖瓣在统计学上仍然较小。由于内皮细胞向间充质转化（EMT）衍生的细胞对NCC的贡献很大，我们进行了近端流出道垫层外植体测定，发现Gata4 ^{G295Ski / wt中的}EMT缺陷胚胎以及细胞增殖缺陷。对突变胚胎的E15.5流出道进行RNA序列分析表明存在疾病状态，并确定了与ECM和细胞迁移以及Wnt信号传导失调有关的基因变化。通过利用具有人类致病突变的小鼠模型，我们证明了GATA4在先天性半月瓣狭窄中的新作用。本文与第一人称联合采访。