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Article: Mutations in Hnrnpa1 cause congenital heart defects

TitleMutations in Hnrnpa1 cause congenital heart defects
Authors
KeywordsCardiovascular disease
Development
Genetics
Heart failure
Organogenesis
Issue Date2018
PublisherAmerican Society for Clinical Investigation.
Citation
JCI insight, 2018, v. 3 n. 2, p. 98555 How to Cite?
AbstractIncomplete 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.
Persistent Identifierhttp://hdl.handle.net/10722/251858
ISSN
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYu, Z-
dc.contributor.authorTang, PL-
dc.contributor.authorWang, J-
dc.contributor.authorBao, S-
dc.contributor.authorShieh, JT-
dc.contributor.authorLeung, AW-
dc.contributor.authorZhang, Z-
dc.contributor.authorGao, F-
dc.contributor.authorWong, SY-
dc.contributor.authorHui, AL-
dc.contributor.authorGao, Y-
dc.contributor.authorDung, N-
dc.contributor.authorZhang, ZG-
dc.contributor.authorFan, Y-
dc.contributor.authorZhou, X-
dc.contributor.authorZhang, Y-
dc.contributor.authorWong, DS-
dc.contributor.authorSham, PC-
dc.contributor.authorAzhar, A-
dc.contributor.authorKwok, PY-
dc.contributor.authorTam, PP-
dc.contributor.authorLian, Q-
dc.contributor.authorCheah, KSE-
dc.contributor.authorWang, B-
dc.contributor.authorSong, Y-
dc.date.accessioned2018-03-21T07:00:39Z-
dc.date.available2018-03-21T07:00:39Z-
dc.date.issued2018-
dc.identifier.citationJCI insight, 2018, v. 3 n. 2, p. 98555-
dc.identifier.issn2379-3708-
dc.identifier.urihttp://hdl.handle.net/10722/251858-
dc.description.abstractIncomplete 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.-
dc.languageeng-
dc.publisherAmerican Society for Clinical Investigation.-
dc.relation.ispartofJCI insight-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCardiovascular disease-
dc.subjectDevelopment-
dc.subjectGenetics-
dc.subjectHeart failure-
dc.subjectOrganogenesis-
dc.titleMutations in Hnrnpa1 cause congenital heart defects-
dc.typeArticle-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailLian, Q: qzlian@hkucc.hku.hk-
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hk-
dc.identifier.emailSong, Y: songy@hku.hk-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityLian, Q=rp00267-
dc.identifier.authorityCheah, KSE=rp00342-
dc.identifier.authoritySong, Y=rp00488-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1172/jci.insight.98555-
dc.identifier.pmid29367466-
dc.identifier.pmcidPMC5821217-
dc.identifier.hkuros289966-
dc.identifier.volume3-
dc.identifier.issue2-
dc.identifier.spage98555-
dc.identifier.epage98555-
dc.identifier.isiWOS:000423337400014-
dc.publisher.placeUnited States-

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