Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways
Open accessAbstract
Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.
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- Authors
- Benson, D. W., Silberbach, G. M., Kavanaugh-McHugh, A., Cottrill, C., Zhang, Y., Riggs, S., Smalls, O., Johnson, M. C., Watson, M. S., Seidman, J. G., Seidman, C. E., Plowden, J., & Kugler, J. D.
- Affiliations
- Medical University of South Carolina (US)
- Oregon Health & Science University (US)
- Vanderbilt University (US)
- University of Kentucky (US)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- University of New Mexico (US)
- Creighton University (US)
- Corresponding author
- Benson, D. Woodrow
- Venue
- Journal of Clinical Investigation
- Published
- 1999-12-01
- Volume
- 104
- Issue
- 11
- Pages
- 1567-1573
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC409866
- OpenAlex
- W2075563634
- Cited by
- 690
- References
- 34
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 22 · 2023: 20 · 2022: 28 · 2021: 28 · 2020: 18 · 2019: 19 · 2018: 25 · 2017: 23 · 2016: 28 · 2015: 22 · 2014: 20 · 2013: 24 · 2012: 31
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p50hl061006-05)
- National Heart, Lung, and Blood Institute (1 P50 HL61006-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
- Keywords
- Nkx2.5, homeodomain transcription factor, congenital heart disease, atrioventricular block, tetralogy of Fallot, atrial septal defect, ventricular septal defect, Ebstein's anomaly, double outlet right ventricle, cardiac morphogenesis, novel mutations
- MeSH terms
- Homeobox Protein Nkx-2.5, DNA Mutational Analysis, Echocardiography, Electrocardiography, Female, Heart, Heart Block, Heart Defects, Congenital, Heterozygote, Humans, Male, Mutation, Pedigree, Phenotype, Transcription Factors, DNA Primers, Homeodomain Proteins, Xenopus Proteins
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