Loss of Gata5 in mice leads to bicuspid aortic valve
Open accessAbstract
Bicuspid aortic valve (BAV), the leading congenital heart disease, occurs in 1%-2% of the population. Genetic studies suggest that BAV is an autosomal-dominant disease with reduced penetrance. However, only 1 gene, NOTCH1, has been linked to cases of BAV. Here, we show that targeted deletion of Gata5 in mice leads to hypoplastic hearts and partially penetrant BAV formation. Endocardial cell-specific inactivation of Gata5 led to BAV, similar to that observed in Gata5-/- mice. In all cases, the observed BAVs resulted from fusion of the right-coronary and noncoronary leaflets, the subtype associated with the more severe valve dysfunction in humans. Neither endocardial cell proliferation nor cushion formation was altered in the absence of Gata5. Rather, defective endocardial cell differentiation, resulting from the deregulation of several components of the Notch pathway and other important endocardial cell regulators, may be the underlying mechanism of disease. The results unravel a critical cell-autonomous role for endocardial Gata5 in aortic valve formation and identify GATA5 as a potential gene responsible for congenital heart disease in humans. Mice with mutated Gata5 alleles represent unique models to dissect the mechanisms underlying degenerative aortic valve disease and to develop much-needed preventive and therapeutic interventions.
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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 [146]
The Introduction states that NOTCH1 mutations had been linked to bicuspid aortic valve in humans, but says NOTCH1 was the only gene linked at the time. The Abstract reports that Gata5 deletion caused bicuspid aortic valve in mice and identifies GATA5 only as a potential human disease gene; it does not establish an association between GATA5 variants and human bicuspid aortic valve. (LLM, conf=0.89)
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References 67 · Cited by 190
Research works printed but not linked: 4
- [7]7. Clementi M, Notari L, Borghi A, Tenconi R. Familial congenital bicuspid aortic valve: a dis- order of uncertain inheritance. Am J Med Genet. 1996;62(4):336-338.
- [21]21. Krantz ID, et al. Jagged1 mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet. 1999;84(1):56-60.
- [44]44. Sans-Coma V, et al. Fusion of valve cushions as a key factor in the formation of congenital bicuspid aortic valves in Syrian hamsters. Anat Rec. 1996; 244(4):490-498.
- [57]57. Singh MK, et al. Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2. Development. 2005;132(12):2697-2707.
- Authors
- Laforest, B., Andelfinger, G., & Nemer, M.
- Affiliations
- Université de Montréal (CA)
- University of Ottawa (CA)
- Corresponding author
- Nemer, Mona
- Venue
- Journal of Clinical Investigation
- Published
- 2011-07-01
- Volume
- 121
- Issue
- 7
- Pages
- 2876-2887
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3223824
- OpenAlex
- W2125727551
- Cited by
- 190
- References
- 67
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 18 · 2018: 10 · 2017: 19 · 2016: 18 · 2015: 14 · 2014: 18 · 2013: 15 · 2012: 13
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- University of Ottawa
- Canadian Institutes of Health Research (MOP36382, 79045_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- GATA5, bicuspid aortic valve, congenital heart disease, aortic valve development, Notch signaling, degenerative aortic valve disease
- MeSH terms
- Animals, Aortic Valve, Embryo, Mammalian, Heart, Heart Defects, Congenital, Humans, Morphogenesis, Myocardium, Signal Transduction, Mice, Knockout, Gene Targeting, Gene Expression Regulation, Developmental, GATA5 Transcription Factor, Mice, Receptors, Notch
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