Mutations in Hnrnpa1 cause congenital heart defects
Zhe Yu, … , Binbin Wang, You-Qiang Song
Zhe Yu, … , Binbin Wang, You-Qiang Song
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e98555. https://doi.org/10.1172/jci.insight.98555.
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Research Article Development Genetics

Mutations in Hnrnpa1 cause congenital heart defects

Abstract

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.

Authors

Zhe Yu, Paul L.F. Tang, Jing Wang, Suying Bao, Joseph T. Shieh, Alan W.L. Leung, Zhao Zhang, Fei Gao, Sandra Y.Y. Wong, Andy L.C. Hui, Yuan Gao, Nelson Dung, Zhi-Gang Zhang, Yanhui Fan, Xueya Zhou, Yalun Zhang, Dana S.M. Wong, Pak C. Sham, Abid Azhar, Pui-Yan Kwok, Patrick P.L. Tam, Qizhou Lian, Kathryn S.E. Cheah, Binbin Wang, You-Qiang Song

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Figure 3

Whole-mount in situ analysis of wild-type embryos stained for Hnrnpa1 mRNA at different embryonic days.

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Whole-mount in situ analysis of wild-type embryos stained for Hnrnpa1 mR...
Wild-type embryos were stained for Hnrnpa1 mRNA, and corresponding sections are shown from arterial pole to venous pole. At E8 and E8.25, staining for Isl1 and Nkx2.5 was also performed. Isl1 labels SHF cardiac progenitors, whereas Nkx2.5 labels both the FHF and SHF lineages. At each stage, results from 1 of 3 representative experiments are displayed. (A) E7; (B) E7.5; (C–E) E8 (2 somite pairs); (F–H) E8.25 (6 somite pairs); and (I) E9.5 (20 somite pairs). (A and B) Expression of Hnrnpa1 in the pre–cardiac crescent stages. Hnrnpa1 mRNA is detected in the ALPM (short arrow). (C) During the cardiac crescent stage, Hnrnpa1 mRNA is expressed in both differentiated myocardium (thin long arrow) and splanchnic mesoderm (wide long arrow). (F) After the formation of primitive heart tube, Hnrnpa1 mRNA maintains its strong expression in the splanchnic mesoderm but with much lower expression level in the differentiated myocardium. (I) In E9.5 wild-type embryo, Hnrnpa1 mRNA continues to be strongly expressed in the splanchnic mesoderm but not in the looped heart tube. FHF, first heart field; SHF, second heart field. Scale bar: 100 μm.