Hnrnpa1 Mutations Cause Congenital Heart Defects

Abstract

Incomplete penetrance of the congenital heart defects (CHDs) was observed in our mouse model. We hypothesized the contribution of another major genetic locus may regulate the manifestation of the CHD phenotypes. We performed genome-wide linkage mapping, fine mapping and high-throughput targeted sequencing and finally identified a recessive CT deletion in exon 5 of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene. Following studies demonstrated the Hnrnpa1ct/ct homozygous mutation alone was responsible for the pathogenesis of the CHDs. Whole mount in situ hybridization showed Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) cardiac lineages at cardiac crescent stage. After heart tube formation, the expression of Hnrnpa1 was only maintained in SHF progenitors. At E9.5, Q-RT-PCR and western blot analyses demonstrated loss of Hnrnpa1 expression in both mRNA and protein levels in Hnrnpa1ct/ct mutants. Dysregulation of a series of cardiac genes was also observed. Hnrnpa1ct/ct homozygous mutation changed the expression pattern of Nkx2.5 and Isl1 and caused cardiac defects at different developmental stages. Lastly, two rare heterozygous mutations of HNRNPA1 were detected in human CHD patients. These findings suggest novel roles of Hnrnpa1 in embryonic cardiac development in both mice and humans.