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 4

Expression of Hnrnpa1 and relative cardiac genes in Hnrnpa1ct/ct mutant embryos at E9.5. GAPDH was used as the internal control for qRT-PCR, and β-Actin was used as the loading control for Western blot, respectively.

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Expression of Hnrnpa1 and relative cardiac genes in Hnrnpa1ct/ct mutant ...
(A) qRT-PCR results for E9.5 embryos. The Hnrnpa1 mRNA level in all 3 genotypes is shown. Six wild-type littermate controls, nine heterozygous mutants, and eight homozygous mutants were used. (B) Three wild-type littermate controls, three homozygous mutants, and four heterozygous mutants were used for Western blot analysis. (C) Total RNA was extracted from isolated pharyngeal region or heart tube respectively at E9.5. qRT-PCR was performed to monitor the expression of both the second heart field (SHF) and heart tube–specific cardiac genes. The number of Hnrnpa1+/+, Hnrnpa1+/ct, and Hnrnpa1ct/ct embryos in the SHF: 8, 5, and 9 for Fgf8, Fgf10, Isl1, Mef2c, and Tbx1; 8, 5, and 8 for Nkx2.5; 8, 6, and 9 for Acvr1, Bmpr1a, and Jag1, respectively. The number of Hnrnpa1+/+, Hnrnpa1+/ct, and Hnrnpa1ct/ct embryos in the heart tube: 8, 8, and 9 for Mlc2a, Mlc2v, and Nkx2.5; 11, 9, and 9 for Mef2c; 11, 11, and 9 for Myocd and SRF, respectively. The values represent mean ± SD in independent samples. **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired 2-tailed t tests with Bonferroni correction.