Spectrum of heart disease associated with murine and human GATA4 mutation

Rajagopal, Satish; Ma, Qing; Obler, Dita; Shen, Jie; Manichaikul, Ani; Tomita‐Mitchell, Aoy; Boardman, Kari; Briggs, Christine; Garg, Vidu; Srivastava, Deepak; Goldmuntz, Elizabeth; Broman, Karl W.; Benson, D. Woodrow; Smoot, Leslie; Pu, William T.

doi:10.1016/j.yjmcc.2007.06.004

Cited by 231 publications

(197 citation statements)

References 33 publications

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“…Screening for mutations of SEMA3C and PLXNA2 may provide further evidence of the involvement of semaphorin-plexin signaling in human OFT defects. It is of note that GATA6 mutations identified in humans were associated with PTA, in contrast with GATA4 mutations, which are commonly associated with atrial and/or ventricular septal defects (20)(21)(22). This result suggests that GATA6 may play a dominant role in OFT development, although Gata6 has been reported to have a redundant role with Gata4 during cardiogenesis (25,(34)(35)(36).…”

Section: Discussionmentioning

confidence: 97%

“…Null mutation of Gata4 in mice results in embryonic lethality because of defects in cardiogenesis (18,19). Mutations of GATA4 in humans were identified to cause CHD characteristic of atrial and/or ventricular septal defects (20,21), and heterozygous mutations of Gata4 in mice recapitulate the human phenotype (22). Systemic ablation of Gata6 in mice also results in embryonic lethality (23), whereas conditional inactivation of Gata6 in the CNC results in perinatal mortality from OFT defects, typically PTA (24).…”

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confidence: 99%

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GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

Kodo

Nishizawa

Furutani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

212

157

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Congenital heart diseases (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although an improved understanding of the genetic causes of CHD would provide insight into the underlying pathobiology, the genetic etiology of most CHD remains unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD characteristic of a severe form of cardiac outflow tract (OFT) defect, namely persistent truncus arteriosus (PTA). Two different GATA6 mutations were identified by systematic genetic analysis using DNA from patients with PTA. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpulmonary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as genetic causes of CHD involving OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling.congenital heart disease ͉ persistent truncus arteriosus ͉ cardiac neural crest C ongenital heart diseases (CHD) constitute a major percentage of clinically significant birth defects with an estimated prevalence of 4-10 per 1,000 live infants (1). Cardiac outflow tract (OFT) defects are estimated to account for approximately 30% of CHD (2) and usually require an intervention during the first year of life. A variety of OFT defects results from disturbance of the morphogenetic patterning of the anterior pole of the heart, which is essential for the establishment of separate systemic and pulmonary circulations in higher vertebrates. Persistent truncus arteriosus (PTA), which is attributed to missing septation of the OFT, is recognized as the most severe phenotype of OFT defect, and is often associated with an unfavorable prognosis because complete surgical repair is not always possible (3). Although an improved understanding of possible genetic causes would provide insight into the pathogenesis of CHD and allow for better assessment of disease risk, prenatal diagnosis, and critical information for disease prevention, the etiology of most CHD, including OFT defects, remains unknown because of the multifactorial nature of the diseases (4-6).Based on animal studies, it appears that abnormal development of cardiac neural crest (CNC) cells, an ectoderm-derived cell lineage, contributes significantly to the pathology of OFT defects (7-12). During early embryogenesis, CNC cells arise from the dorsal neural tube and migrate ventrally as mesenchymal cells to populate the OFT, where they coalesce to form the aorticopulmonary septum, which divides the single truncus arteriosus (embryonic OFT) into the aorta and pulmonary artery, resulting in the establishment of separate systemic and pulmonary c...

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

Kodo

Nishizawa

Furutani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

212

157

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“…During the course of this study, more germ line heterozygous GATA4 mutations have since been reported (Rajagopal et al 2007, Reamon-Buettner et al 2007. Interestingly, some of these occur in the GATA4 intronic sequences or the 3 0 non-translated region of the GATA4 mRNA.…”

Section: Discussionmentioning

confidence: 84%

“…Thus, far, only fully penetrant germ line GATA4 mutations have been reported as a result of screening large families where congenital heart defects are present in more than one generation. Recently, the screening of large cohorts of individuals presenting cardiac malformations uncovered the first non-fully penetrant GATA4 mutations (Rajagopal et al 2007. Given the identification of these novel GATA4 mutations, a similar screen of individuals presenting reproductive abnormalities, and especially that involving gonadal sex reversal is both warranted and needed.…”

Section: Discussionmentioning

confidence: 99%

The effect of human GATA4 gene mutations on the activity of target gonadal promoters

Taniguchi¹,

Viger

2008

Journal of Molecular Endocrinology

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GATA transcription factors are crucial regulators of cell-specific gene expression in many tissues including the gonads. Although clinical cases of reproductive dysfunction have yet to be formally linked to GATA gene mutations, they have begun to be reported in other systems. Heterozygous GATA4 mutations have been associated with cases of congenital heart defects. Little is known, however, about the effect of these mutations on gonadal gene transcription. Since individuals carrying these mutations do not appear to suffer from gross reproductive defects, we hypothesized that this might be due to the differential transcriptional properties of the mutant proteins on heart versus gonadal target genes. Five mutations (S52F, E215D, G295S, V266M, and E359X) were recreated in the rat GATA4 protein.Several parameters were used to analyze the transcriptional properties of the mutants: activation of known gonadal target promoters (Star, Cyp19a1, and Inha), DNA binding, and interaction with GATA4 transcriptional partners. Three mutations (S52F, G295S, and E359X) reduced GATA4 transcriptional activity on the different gonadal promoters. With the exception of the G295S mutant, which showed a significant loss of DNA-binding affinity, the decrease in activity of the other GATA4 mutants was not associated with a change in DNA binding. All GATA4 mutants retained their ability to interact and cooperate with their major gonadal partners (NR5A1 and NR5A2) thereby compensating in part for the loss in intrinsic GATA4 transcriptional activity. Thus, unlike the heart, where the GATA4 mutations have deleterious effects, our data suggest that they would have a lesser impact on gonadal gene transcription and function.

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“…The null mutation of GATA-4 results in the abnormal ventral folding of the embryo, failure to form a single ventral heart tube, and lethality by embryonic day (E) 10.5 (6,7). In humans, mutations in GATA-4 result in congenital cardiomyopathies, including valve and septal defects (8,9). Both conditional knockout mice lacking GATA-4 in specific cardiomyocytes, as well as transgenic mice expressing only 30% of the normal levels of GATA-4 in the heart, display atrioventricular canal defects and a hypoplastic ventricular myocardium.…”

Section: Introductionmentioning

confidence: 99%

GATA-4 promotes the differentiation of P19 cells into cardiac myocytes

Chen²,

Liu³

et al. 2010

Int J Mol Med

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Abstract. The aim of this study was to investigate the effects of GATA-4 on the differentiation of P19 cells into cardiomyocytes and to examine the relationship between GATA-4 and cardiomyocytes. We constructed vectors to overexpress and silence GATA-4. These vectors, as well as empty ones were transfected into P19 cells. Subsequently, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were performed. The morphology of P19 cells during differentiation was observed using an inverted microscope. Total RNA was extracted from P19 cells. We used real-time PCR to evaluate the expression levels of 6 genes: GATA-4, GATA-6, transthyretin (TTR), ·-fetoprotein (AFP), Nkx2.5, and ·-myosin heavy chain (·-MHC). The gene expression pattern of these 6 genes is graphically shown for each group. The GATA-4 mRNA level in cells overexpressing GATA-4 was notably higher than that in the controls, whereas the levels in the controls were notably higher than those in the GATA-4-silenced P19 cells. The cell lines overexpressing GATA-4 expressed higher levels of Nkx2.5 and ·-MHC than the controls. However, the controls expressed higher levels of AFP, GATA-6 and TTR than the cells overexpressing GATA-4. The RNAi group expressed lower levels of TTR, Nkx2.5, and ·-MHC than the controls, but there were no differences in the RNAi group and the controls with regard to the expression levels of AFP and GATA-6. The gene expression pattern in the cells overexpressing GATA-4 was biased toward the Nkx2.5 and ·-MHC. On the other hand, the gene expression pattern in GATA-4-silenced cells and the controls was biased toward the TTR and AFP. The overexpression of GATA-4 enhances the differentiation of P19 cells into cardiac myocytes, whereas its down-regulation suppresses this trend.

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Spectrum of heart disease associated with murine and human GATA4 mutation

Cited by 231 publications

References 33 publications

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

The effect of human GATA4 gene mutations on the activity of target gonadal promoters

GATA-4 promotes the differentiation of P19 cells into cardiac myocytes

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