Trends in Molecular Medicine
Research FocusTranscription factor cascades in congenital heart malformation
Section snippets
GATA-4: a crucial transcription factor in mammalian cardiogenesis
Human cytogenetic studies, as well as gene expression and transgenic studies in animals, have justified a role for GATA-4, a member of the conserved GATA zinc-finger transcription factor family, during cardiogenesis. In humans, loss of the chromosome 8p segment containing GATA-4 is associated with CHMs [14]. During murine cardiogenesis, Gata-4 is expressed in the atrial and ventricular myocardia, endocardium, endocardial cushions and outflow tract [15]. Mice with complete loss of Gata-4 die in
Human phenotypes and transcription factor genotypes
Regardless of the ambiguity of the GATA-4–TBX5 interaction, addition of GATA-4 to an NKX2.5 and TBX5 co-dependent set of embryonic cascades that regulate cardiac septation is important. Crucial to the placement of GATA-4 within this network is an appreciation of the similarities and dissimilarities of clinical phenotypes associated with their human mutations. Developmental mechanisms and expression patterns of certain genes are not always conserved between humans and animal models [23].
Should consideration of GATA-4 mutations be incorporated into clinical care?
Because GATA-4 mutations have not previously been demonstrated to cause human disease, these new findings prompt consideration of their potential clinical application. Should GATA-4 genotyping be considered for inclusion in the clinical care of individuals with all CHMs or just those with septation defects? Broad-based population and individual patient screening for GATA-4 mutations is probably premature without a better understanding of the prevalence, penetrance and genotype–phenotype
References (29)
A new gene, EVC2, is mutated in Ellis-van Creveld syndrome
Mol. Genet. Metab.
(2002)- et al.
Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6
Dev. Biol.
(2003) GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut
J. Biol. Chem.
(1994)TBX5 nuclear localization is mediated by dual cooperative intramolecular signals
J. Mol. Cell. Cardiol.
(2003)- et al.
Prenatal diagnosis
N. Engl. J. Med.
(1993) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5
Nature
(2003)- et al.
Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus
Am. J. Med. Genet.
(2000) Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome
Nat. Genet.
(1997)Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family
Nat. Genet.
(1997)Congenital heart disease caused by mutations in the transcription factor NKX2-5
Science
(1998)
Okihiro syndrome is caused by SALL4 mutations
Hum. Mol. Genet.
Mutations in the human Jagged1 gene are responsible for Alagille syndrome
Nat. Genet.
Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
Nat. Genet.
Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis
Nat. Genet.
Cited by (20)
Congenital heart disease in monozygotic twins
2020, Developmental and Fetal Origins of Differences in Monozygotic Twins: From Genetics to Environmental FactorsMaintenance of adult cardiac function requires the chromatin factor Asxl2
2012, Journal of Molecular and Cellular CardiologyCitation Excerpt :Transcriptional regulation plays critical roles in heart development and function [1–6].
Lentivirus-mediated wnt11 gene transfer enhances cardiomyogenic differentiation of skeletal muscle-derived stem cells
2011, Molecular TherapyCitation Excerpt :NKx2.5 and GATA4 are two critical transcription factors expressed when cells undergo a cardiac lineage commitment. It is known that Nkx2.5, α-MHC, β-MHC, and TnI are downstream cardiac lineage genes of GATA4 and that BNP is a downstream gene of NKx2.5.35 A recent study demonstrated that Nkx2.5 upregulates GATA4 expression but suppresses β-catenin expression,36 the latter is likely to increase noncanonical Wnt signaling activity which is necessary for differentiation.
Stat3 directly controls the expression of Tbx5, Nkx2.5, and GATA4 and is essential for cardiomyocyte differentiation of P19CL6 cells
2010, Journal of Biological ChemistryCitation Excerpt :Among these Stat3 target genes, we identified three genes that are cardiac differentiation markers: Tbx5, Nkx2.5, and GATA4 (18, 21, 22). These genes are required for cardiac differentiation and development, and mutations in any one of the three genes can lead to congenital heart malformation (23–29). Tbx5 and Nkx2.5 interact to promote cardiomyocyte differentiation through regulation of the cardiac-specific natriuretic peptide precursor type A (Nppa) gene (30).
Hormonal regulation of cardiac KCNE2 gene expression
2008, Molecular and Cellular Endocrinology