Mutations in Hnrnpa1 cause congenital heart defects

Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frames...

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Bibliographic Details
Published in:	JCI insight Vol. 3; no. 2
Main Authors:	Yu, Zhe, Tang, Paul Lf, Wang, Jing, Bao, Suying, Shieh, Joseph T, Leung, Alan Wl, Zhang, Zhao, Gao, Fei, Wong, Sandra Yy, Hui, Andy Lc, Gao, Yuan, Dung, Nelson, Zhang, Zhi-Gang, Fan, Yanhui, Zhou, Xueya, Zhang, Yalun, Wong, Dana Sm, Sham, Pak C, Azhar, Abid, Kwok, Pui-Yan, Tam, Patrick Pl, Lian, Qizhou, Cheah, Kathryn Se, Wang, Binbin, Song, You-Qiang
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 25-01-2018
Subjects:	Heart failure Development Cardiovascular disease Genetics Organogenesis
Online Access:	Get full text
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Summary:	Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: Z. Yu, P.L.F. Tang, and J. Wang are co–first authors.
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.98555