GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

Garg, Vidu; Kathiriya, Irfan S.; Barnes, R. Bowling; Schluterman, Marie K.; King, Isabelle N.; Butler, Cheryl; Rothrock, Caryn R.; Eapen, Reenu S.; Hirayama‐Yamada, Kayoko; Joo, Kunitaka; Matsuoka, Rumiko; Cohen, Jonathan C.; Srivastava, Deepak

doi:10.1038/nature01827

Cited by 1,088 publications

(954 citation statements)

References 29 publications

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“…In addition, GATA4 loss by deletion of chromosome 8p or mutation has been implicated as a predisposing factor in patients with congenital heart disease (Garg et al, 2003;Reamon-Buettner et al, 2007). In our ongoing study in GBMs, the most malignant and devastating brain tumor, we observed a high loss of GATA4.…”

Section: Discussionmentioning

confidence: 57%

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

et al. 2009

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The GATA transcription factors consist of six family members, which bind to the consensus DNA-binding element, W-GATA-R, and are poorly characterized in the central nervous system (CNS). Using retroviral gene trapping on transgenic mouse glioma models, we identified GATA6 to be a novel tumor suppressor gene in glioblastoma multiforme. We now show GATA4, a family member of GATA6, to be expressed in the neurons and glia of normal murine and human embryonic and adult CNS. Silencing GATA4 in normal astrocytes did not alter their growth properties. In contrast, knockdown of Gata4 in p53 null non-transformed murine astrocytes induced transformation, with increased proliferation and resistance to chemotherapy or radiation-induced apoptosis. Furthermore, GATA4 expression was lost in a panel of human malignant astrocytoma cell lines. GATA4 overexpression in normal human and murine astrocytes resulted in a cell cycle block in G1 phase, with increased apoptosis. Mechanistically, GATA4 was a transcriptional inducer of the cyclin-dependent kinase inhibitor, p15INK4B, leading to the attenuation of cyclin D1. GATA4 expression was also induced by transforming growth factor-b, leading to the inhibition of astrocyte proliferation. Collectively, we show that GATA4 is expressed in the embryonic and adult CNS and acts as a negative regulator of astrocyte proliferation and growth.

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Section: Discussionmentioning

confidence: 57%

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

et al. 2009

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“…7,20,21,27,28 A disrupted interaction between GATA4 and TBX5 is involved in ASDs in both humans and mice. 4,19 Similarly, a link between GATA6 and TBX5 has been recognized, and compound heterozygosity of both genes results in defects in myocardial development. 19 Although no direct interactions have been reported between GATA6 TAD region and other transcriptional factors, such as GATA4 and TBX5, the general interactions between those transcriptional factors may aid in our understanding of the mechanistic basis of ASD because of GATA6 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…2 Recent studies have identified a series of genes that contribute to inherited and sporadic CHD, and most of these genes encode cardiac transcription factors such as Nkx2.5, TBX5 and GATA4. [3][4][5][6] GATA family members (GATA1-6) contain two zinc-finger domains that bind to a consensus site, (A/T) GATA (A/G), and mediate interactions with diverse factors. 7 GATA4, 5 and 6 are expressed early in the heart tissue and endodermal derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…9 Numerous mutations in GATA4 have been recognized in a wide range of cases, including tetralogy of Fallot (TOF), pulmonary stenosis, atrial septal defects (ASDs), ventricular septal defects, atrioventricular septal defects and patent ductus arteriosus. 4,[10][11][12][13][14][15][16][17] GATA6 is another member of the GATA family with expression and functions that overlap with GATA4 during cardiovascular development. 7 Recent experiments in animals have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, highlighting the potential involvement of GATA6 mutations in the pathogenesis of human CHD.…”

Section: Introductionmentioning

confidence: 99%

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A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.

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“…Most CHD occur sporadic, but in recent years an increasing number of familial cases with various types of CHD have been reported. [2][3][4] Although mutations in several genes have been identified in a small subset of patients and families with CHD, eg, NKX2.5, 2 GATA4 3 and NOTCH1, 5 the mechanisms underlying human cardiogenesis and CHDs remain largely unknown. Some CHD patients and families also display cardiac arrhythmias, which can occur due to the anatomical defect itself or sometimes due to surgical interventions.…”

Section: Introductionmentioning

confidence: 99%

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

et al. 2011

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Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

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GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

Cited by 1,088 publications

References 29 publications

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

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