Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.
Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.
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鉴定具有介导先天性心脏病中 MicroRNA 功能障碍潜力的新型单核苷酸变体
DOI：
10.3389/fcvm.2021.739598
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发表时间：
2021
影响因子：
3.6
通讯作者：
Huang ZP
中科院分区：
文献类型：
--
作者：
Liu W;Cheng L;Chen K;Wu J;Peng R;Tang YL;Chen J;Yang Y;Li P;Huang ZP
先天性心脏病（CHD）是最常见的人类出生缺陷。我们之前的研究表明，心脏神经嵴细胞 (NCC) 中的 microRNA (miRNA) 功能障碍可能与人类冠心病的发病机制有关，该细胞有助于心脏和相连大血管的发育。在这项研究中，我们试图进一步寻找来自 CHD 患者的致病单核苷酸变异 (SNV)，这些变异在 CHD 发病机制中介导 miRNA 对下游靶基因的错误调节。结果，从 CHD 队列中总共检测到 2,925 个 3'UTR SNV。与此同时，我们分析了心脏 NCC 中 miRNA 的表达，发现了 201 个表达的 miRNA。结合这些数据的分析进一步鉴定出三个3'UTR SNV，包括NFATC1 c.*654C>T、FGFRL1 c.*414C>T和CTNNB1 c.*729_*730insT，它们导致miRNA介导的基因调控功能失常。这种失调现象得到了实验的进一步验证。因此，我们的研究表明，心脏NCC中miRNA介导的基因失调可能是先天性心脏病的重要病因，这可能为先天性心脏病的诊断和治疗研究带来新的方向。
Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream target genes in the pathogenesis of CHDs. As a result, a total of 2,925 3′UTR SNVs were detected from a CHD cohort. In parallel, we profiled the expression of miRNAs in cardiac NCCs and found 201 expressed miRNAs. A combined analysis with these data further identified three 3′UTR SNVs, including NFATC1 c.*654C>T, FGFRL1 c.*414C>T, and CTNNB1 c.*729_*730insT, which result in the malfunction of miRNA-mediated gene regulation. The dysregulations were further validated experimentally. Therefore, our study indicates that miRNA-mediated gene dysregulation in cardiac NCCs could be an important etiology of congenital heart disease, which could lead to a new direction of diagnostic and therapeutic investigation on congenital heart disease.