Mutations in Hnrnpa1 cause congenital heart defects.

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

doi:10.1172/jci.insight.98555

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.

Highlights

In humans, nearly 1% of newborns are affected by congenital heart defects (CHDs), and epidemiological studies have suggested significant genetic contribution to the manifestation of CHDs [1,2,3]
We hypothesized that the genetic locus for CHD is located beyond 98.95 Mb toward the end of chromosome 15, where the IIA-null alleles from C57-IIA+/− mice are predominantly transmitted to affected individuals
Since we did not observe any cardiac abnormalities in the mice with genotype of 129-IIA−/− in embryonic or postnatal stages (Supplemental Table 1), and assuming that the ES cell used for generating the IIA-null mutant was a hybrid of 129S1/SvImJ and 129X1/SvJ, we hypothesized that this segment of DNA contained a mutation that caused CHD, which was generated during the targeted disruption of Col2a1 and cosegregated with the IIA-null locus

Summary

Introduction

Nearly 1% of newborns are affected by congenital heart defects (CHDs), and epidemiological studies have suggested significant genetic contribution to the manifestation of CHDs [1,2,3]. We elucidated the function of IIA in IIA procollagen-deficient mice, generated by deleting exon II of Col2a1 in a hybrid genetic background [8].

Methods

Results

Discussion

Conclusion