Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

Wangkai Liu,Jinghai Chen,Liangping Cheng,Zhan-Peng Huang,Ken Chen,Yuedong Yang,Jialing Wu,Peiqiang Li,Yan-Lai Tang,Rui Peng

doi:10.3389/fcvm.2021.739598

Abstract

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.

Highlights

Congenital heart defects (CHDs) represent the most common human birth defects
Environmental factors are involved in the pathogenesis of CHDs, genetic mutation—both inherited mutation and de novo mutation—is the major cause of CHDs
Huge efforts have been spent on investigating the genetic cause responsible for the CHDs we observed, and some mutations have been successfully linked to syndromes associated with CHDs

Summary

Introduction

Congenital heart defects (CHDs) represent the most common human birth defects. Among the spectrum of CHDs, malformations in the aortic arch artery and outflow tract comprise nearly 40% of CHDs, and ventricular septal defect is estimated to account for about 30% of CHDs. There is a subset of NCCs defined as cardiac NCCs, which arise from the dorsal neural tube between the midotic placode and the caudal limit of somite 3 They migrate into pharyngeal arches 3, 4, and 6 [1]. Studies have revealed that several factors, including Wnt [5], Fgf [6], Tgf-β [7], BMP [8] families, and Shh [9], and their signaling pathways are critical to the development of neural crest derivatives Disruption of these signaling pathways in NCCs in a mouse model leads to multiple developmental defects, which assemble CHDs found in human patients

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