Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.
Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.
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DOI：
10.1016/j.cels.2022.09.001
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发表时间：
2022-11-16
期刊：
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管有很强的遗传成分，但只有少数基因在先天性心脏病中被发现。我们引入了系统分析来揭示CHD突变生物网络的隐藏组织，并利用网络分析来整合蛋白质相互作用组，患者外显子组和发育中心脏的单细胞转录组。我们确定了一个CHD网络调节心脏发育，并观察到一个子网络也调节胎儿大脑发育，从而提供了CHD和神经发育条件之间的临床共病的机制见解。在小规模，我们实验验证了几种蛋白质的未表征的心脏功能。在全球范围内，我们的研究揭示了该网络的发育动力学，并观察到其与左心发育不全综合征（HLHS）的相关性，这进一步得到了HLHS内皮细胞网络失调的支持。总的来说，我们的工作确定了以前未表征的CHD因素，并提供了适用于研究许多其他复杂疾病的可推广框架。本文的透明同行评审过程的记录包含在补充信息中。一个系统生物学的方法来揭示先天性心脏病的突变结构。蛋白质相互作用网络的突变精细映射揭示了解释CHD和神经发育障碍之间的共病的分子组分，并涉及左心发育不良综合征的内皮功能。
Despite a strong genetic component, only a few genes have been identified in congenital heart diseases. We introduced systems analyses to uncover the hidden organization on biological networks of mutations in CHD, and leveraged network analysis to integrate the protein interactome, patient exomes and single-cell transcriptomes of the developing heart. We identified a CHD network regulating heart development, and observed that a sub-network also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHD and neurodevelopmental conditions. At a small scale, we experimentally verified uncharacterized cardiac functions of several proteins. At a global scale, our study revealed developmental dynamics of the network and observed its association with hypoplastic left heart syndrome (HLHS), which was further supported by the dysregulation of the network in HLHS endothelial cells. Overall, our work identified previously uncharacterized CHD factors and provided a generalizable framework applicable to studying many other complex diseases. A record of this paper’s Transparent Peer Review process is included in the Supplemental Information. A systems biology approach was developed to reveal the mutational architecture in congenital heart defects. Fine-mapping of mutations onto the protein interaction network uncovered molecular components explaining the comorbidity between CHD and neurodevelopmental disorders and implicating endothelial functions in the hypoplastic left heart syndrome.
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