GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve
Open accessAbstract
Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans worldwide and is responsible for substantial morbidity and mortality. Accumulating evidence has demonstated that genetic risk factors are involved in the pathogenesis of BAV. However, BAV is genetically heterogeneous and the genetic basis underlying BAV in a large number of patients remains unknown. In the present study, the coding regions and splice junction sites of the GATA5 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, was sequenced initially in 110 unrelated patients with BAV. The available relatives of the mutation carriers and 200 unrelated healthy individuals used as controls were subsequently genotyped for GATA5. The functional effect of the mutations was characterized by using a luciferase reporter assay system. As a result, two novel heterozygous GATA5 mutations, p.Y16D and p.T252P, were identified in two families with autosomal dominant inheritance of BAV, respectively. The variations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily. Functional assays revealed that the two GATA5 mutants were associated with significantly reduced transcriptional activity compared with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA5 loss-of-function mutations with enhanced susceptibility to BAV, providing novel insight into the molecular mechanism involved in human BAV and suggesting a potential role for the early prophylaxis and personalized treatment of this common congenital heart disease.
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Variants of NOTCH1 and GATA5 have been associated with bicuspid aortic valves in humans.
“So far, variants of NOTCH1 and GATA binding protein 5 (GATA5) have been associated with bicuspid aortic valves in humans97;146;147.”
From Calcific aortic stenosis (2016) · cites this paper as [147]
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- Authors
- SHI, L.-M., TAO, J.-W., QIU, X.-B., WANG, J., YUAN, F., XU, L., LIU, H., LI, R.-G., XU, Y.-J., WANG, Q., ZHENG, H.-Z., LI, X., WANG, X.-Z., ZHANG, M., QU, X.-K., & YANG, Y.-Q.
- Affiliations
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Venue
- International Journal of Molecular Medicine
- Publisher
- Spandidos Publications
- Published
- 2014-03-14
- Volume
- 33
- Issue
- 5
- Pages
- 1219-1226
- ISSN
- 1107-3756 (ISSN-L)
- 1791-244X
- OpenAlex
- W2040866440
- Cited by
- 95
- References
- 82
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 6 · 2017: 14 · 2016: 8 · 2015: 11 · 2014: 7
- FWCI
- 9.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Keywords
- bicuspid aortic valve, GATA5, loss-of-function mutations, congenital heart disease, zinc finger transcription factor, autosomal dominant inheritance, novel mutations, transcriptional activity, genetic susceptibility, aortic valve development
- MeSH terms
- Bicuspid Aortic Valve Disease, Adult, Aortic Valve, Female, Heart Defects, Congenital, Heart Valve Diseases, Humans, Male, Mutation, Pedigree, Genetic Predisposition to Disease, GATA5 Transcription Factor, Young Adult
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