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 1

Identification of a de novo CT deletion in Hnrnpa1.

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Identification of a de novo CT deletion in Hnrnpa1. (A) Chromosome 15–li...
(A) Chromosome 15–linked congenital heart defect (CHD) locus. The x axis represents the relative location of markers on a chromosome, and the y axis represents the –log(P) for nonparametric linkage–ALL (NPL-ALL) scores and BLOCK recessive scores. (B) Transmission disequilibrium test (TDT) for the combined data set from E9.5 and P0. We genotyped 40 more SNP markers for the region of chr15:90.7–100.6 Mb. Significant association with the heart defect phenotype was found starting from chr15:98.95 Mb, consistent with the NPL analysis in the embryonic lethality data set. We hypothesized the new CHD locus should be located beyond 98.95 Mb, where alleles from the C57BL/6N mutant were first shown to be predominately transmitted to affected individuals. We defined this segment, which independently assorted with the IIA genotype, as a breakpoint between Col2a1 and the new CHD locus. The breakpoint was shown to be flanked by markers rs8277842 at 98.6 Mb and rs3708604 at 98.95 Mb on chromosome 15. The green arrow pointing to the left indicates the position of Col2a1 and the blue arrow pointing to the right indicates the breakpoint. For both A and B, P < 0.001 was considered as significant. (C) Haplotype analysis in affected litters. The same region of the TDT analysis presented in chr15:90.8–100.6 Mb is shown. The haplotype information (154.4) is mainly inferred from rs6284372. In this pedigree, there are 8 F1, all bearing a heterozygous configuration for this segment. F2 collected from intercrossing F1 provide 3 main haplotypes: 154.4/154.4, 154.4/ICR-C14, and ICR-C14/ICR-C14. Among 53 individuals in F2, all 11 affected individuals was found to be carrying the 154.4/154.4 haplotype; while the unaffected individuals have a distribution of 5:24:13 for the 3 mentioned haplotype configurations, respectively. Markers do not appear to segregate in chr15:90.8–98.6 Mb, probably due to our selection of the IIA-null allele for a procollagen IIA–deficient mutant mouse line. Therefore, the haplotype for this region was inferred with an assumption that no recombination happened in the region with the pedigree under study. (D) Targeted sequencing of the 1.2-Mb candidate region detected a 2-base deletion in Hnrnpa1 gene. A screen shot from the IGV browser shows the deletion of CT in Hrnrnpa1 in a heterozygous mouse. (E) Sanger sequencing confirmed the presence of CT deletion in Hnrnpa1.