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是导致 4q 缺失综合征患者心脏畸形的遗传因素。

is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients.

机构信息

Neonatal Intensive Care Unit, Shanghai Pediatric Congenital Heart Disease Institute and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Shanghai Pediatric Congenital Heart Disease Institute and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Elife. 2021 Jun 8;10:e67481. doi: 10.7554/eLife.67481.

DOI:10.7554/eLife.67481
PMID:34099102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8186900/
Abstract

Chromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions without known CHD genes suggests unknown CHD genes within these intervals. Here, we have shown that knockdown of , a 4q interval gene, disrupted sarcomeric integrity of cardiomyocytes and caused reduced cardiomyocyte number in human embryonic stem cell differentiation model. Molecular analyses revealed decreased expression of second heart field (SHF) marker genes and impaired NOTCH and SHH signaling in knockdown cells. Exogenous SHH rescued knockdown-induced cardiomyocyte differentiation defects. mouse mutants had atrial septal hypoplasia/aplasia or double atrial septum (DAS) derived from impaired posterior SHF with a similar expression alteration. Rare variants were significantly enriched in a cohort of 300 CHD patients. Our findings indicate that is a regulator of SHF development and its variants contribute to CHD pathogenesis. The presence of DAS in hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.

摘要

4q 染色体缺失是先天性心脏病 (CHD) 患者中最常见的基因组失衡事件之一。然而，一部分与 CHD 相关的 4q 缺失区域内没有已知的 CHD 基因，这表明这些区域内存在未知的 CHD 基因。在这里，我们已经表明，敲低 4q 区间基因 ，会破坏心肌细胞的肌节完整性，并导致人类胚胎干细胞分化模型中心肌细胞数量减少。分子分析显示，敲低细胞中第二心区 (SHF) 标记基因的表达降低，并损害 NOTCH 和 SHH 信号。外源性 SHH 挽救了 敲低诱导的心肌细胞分化缺陷。 鼠突变体具有房间隔发育不全/缺失或双房间隔 (DAS)，这是由后部 SHF 受损引起的，具有相似的表达改变。在 300 名 CHD 患者的队列中，罕见的 变体明显富集。我们的研究结果表明， 是 SHF 发育的调节剂，其变体导致 CHD 的发病机制。在 心脏中存在 DAS 揭示了与反常性血栓栓塞相关的这种罕见异常的第一个分子病因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/9ceed4d6a19a/elife-67481-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/153dd750703b/elife-67481-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/5bf1a2b23ad1/elife-67481-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/9ceed4d6a19a/elife-67481-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/153dd750703b/elife-67481-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/d0fe135aabe1/elife-67481-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/80e4894bc20b/elife-67481-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/64c98a4cb1a1/elife-67481-fig1-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/2613f3e874f0/elife-67481-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/ffea6a5f8b46/elife-67481-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/3ea2c3471d31/elife-67481-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e321/8186900/5bf1a2b23ad1/elife-67481-fig4.jpg
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