Mutations in Hnrnpa1 cause congenital heart defects

Yu，Zhe1; Tang，Paul Lf1; Wang，Jing2; Bao，Suying1; Shieh，Joseph T.3; Leung，Alan Wl1; Zhang，Zhao4; Gao，Fei4; Wong，Sandra Yy1; Hui，Andy Lc1; Gao，Yuan1; Dung，Nelson1; Zhang，Zhi Gang1; Fan，Yanhui1; Zhou，Xueya5; Zhang，Yalun1; Wong，Dana Sm1; Sham，Pak C.5,6,7; Azhar，Abid8; Kwok，Pui Yan9; Tam，Patrick Pl10; Lian，Qizhou4; Cheah，Kathryn Se1; Wang，Binbin2; Song，You Qiang1,6,7,11,12

2018-01-25

10.1172/jci.insight.98555

JCI Insight   影响因子和分区

2324-7703

2379-3708

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.

Cardiovascular disease Development Genetics Heart failure Organogenesis

SCI

英语

其他

2-s2.0-85062247804

Scopus

1.School of Biomedical Sciences,Joint Laboratories of Matrix Biology and Diseases,University of Hong Kong,Hong Kong,China
2.National Research Institute for Family Planning,Beijing,China
3.Institute for Human Genetics and Department of Pediatrics,School of Medicine,University of California San Francisco,San Francisco,United States
4.Department of Medicine and Ophthalmology,Nigeria
5.Department of Psychiatry,
6.Centre for Genome Sciences,
7.State Key Laboratory for Cognitive and Brain Sciences,University of Hong Kong,Hong Kong,China
8.Institute of Biotechnology & Genetic Engineering,University of Karachi,Karachi,Pakistan
9.Cardiovascular Research Institute,School of Medicine,University of California San Francisco,San Francisco,United States
10.Embryology Unit,Children's Medical Research Institute,School of Medical Sciences,University of Sydney,Westmead,Australia
11.University of Hong Kong Shenzhen Institute of Research and Innovation and,
12.University of Hong Kong-Southern University of Science and Technology Joint Laboratories of Matrix Biology and Diseases,University of Hong Kong,Hong Kong,China

Yu，Zhe,Tang，Paul Lf,Wang，Jing,et al. Mutations in Hnrnpa1 cause congenital heart defects[J]. JCI Insight,2018,3(2).

Yu，Zhe.,Tang，Paul Lf.,Wang，Jing.,Bao，Suying.,Shieh，Joseph T..,...&Song，You Qiang.(2018).Mutations in Hnrnpa1 cause congenital heart defects.JCI Insight,3(2).

Yu，Zhe,et al."Mutations in Hnrnpa1 cause congenital heart defects".JCI Insight 3.2(2018).