HGNC Approved Gene Symbol: GATA4
SNOMEDCT: 86299006; ICD10CM: Q21.3; ICD9CM: 745.2;
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:11,676,935-11,760,002 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | ?Testicular anomalies with or without congenital heart disease | 615542 | Autosomal dominant | 3 |
| Atrial septal defect 2 | 607941 | Autosomal dominant | 3 | |
| Atrioventricular septal defect 4 | 614430 | Autosomal dominant | 3 | |
| Tetralogy of Fallot | 187500 | Autosomal dominant | 3 | |
| Ventricular septal defect 1 | 614429 | Autosomal dominant | 3 |
The GATA-binding proteins are a group of structurally related transcription factors that control gene expression and differentiation in a variety of cell types. Members of this family of DNA-binding proteins recognize a consensus sequence known as the 'GATA' motif, which is an important cis-element in the promoters of many genes (Arceci et al., 1993). All GATA-binding proteins contain 1 or 2 zinc finger motifs of the distinctive form CXNCX(17)CNXC (Evans et al., 1988). GATA1 (305371), the founding member of the family, is expressed in erythroid cells, megakaryocytes, and other hematopoietic cells. It regulates expression of genes critical for erythroid development, such as the globin genes. GATA2 (137295) is expressed in hematopoietic cells and numerous other cell types. This factor has been implicated in the regulation of endothelial gene expression and hematopoiesis. GATA3 (131320) is expressed in brain and T cells and appears to control expression of T-cell receptor genes. A fourth member of the GATA-binding family, GATA4, is expressed in adult vertebrate heart, gut epithelium, and gonads. During fetal development, GATA4 is expressed in yolk sac endoderm and cells involved in heart formation (Arceci et al., 1993). Promoter and enhancer studies suggested that this factor may regulate genes critical for myocardial differentiation and function, including troponin C (191040), cardiac alpha-myosin heavy chain (MYH6; 160710), and brain-type natriuretic factor (600295) (Durocher et al., 1997).
Arceci et al. (1993) cloned the mouse GATA4 cDNA by screening a 6.5-day embryonic library with primers based on the conserved zinc finger domains. The 50-kD predicted protein contains 2 zinc fingers and, when expressed in cell culture, activated appropriate reporter constructs.
By screening a human heart cDNA library, Huang et al. (1995) isolated a full-length cDNA clone for GATA4. Northern blot analysis revealed that the 4.4-kb transcript was more highly expressed in adult heart than in fetal heart. They concluded that GATA4 may regulate a set of cardiac-specific genes and play a crucial role in cardiogenesis.
By Southern blot analyses of genomic DNAs from human/rodent somatic cell hybrid lines, White et al. (1995) mapped the GATA4 gene to the proximal region of 8p. Huang et al. (1996) used fluorescence in situ hybridization to assign the human GATA4 gene to 8p23.1-p22.
By analysis of genomic DNAs from an interspecific backcross, White et al. (1995) mapped the mouse Gata4 gene to chromosome 14, closely linked to the locus for clusterin (185430). This mapping assignment placed the Gata4 gene in the vicinity of the mouse Ds (disorganization) locus, a dominant gain-of-function mutation affecting embryonic development. White et al. (1995) speculated that Ds is caused by a mutation in the Gata4 gene, ectopic expression of Gata-4, or a mutation in another lineage determination gene closely linked to Gata4.
Molkentin et al. (1994) reported that GATA4 regulates the expression of MYH6. They identified a GATA motif located within the proximal promoter region of the MYH6 gene. Huang et al. (1995) likewise identified a putative GATA-binding site within the 5-prime flanking sequence of the MYH6 gene.
Hasegawa et al. (1997) presented evidence implicating GATA4 as a mediator of changes in gene expression associated with cardiac hypertrophy. The authors injected a luciferase reporter construct driven by the cardiac beta-myosin heavy chain (MYH7; 160760) promoter region into rat myocardium in vivo. Cardiac hypertrophy was induced by surgical aortic constriction. Reporter gene expression in hypertrophic myocardium after 23 days was 3 times higher than that in sham controls (P less than 0.005); however, mutation of the GATA motif markedly reduced this response. Hasegawa et al. (1997) concluded that interaction between GATA4 and the GATA element plays a role in the transcriptional activation of MYH7 during pressure overload cardiac hypertrophy.
Similar evidence implicating GATA4 as a mediator of cardiac hypertrophy was presented by Herzig et al. (1997). Using a luciferase reporter gene containing the AGTR1 promoter (106165), Herzig et al. (1997) demonstrated a 1.6-fold increase in luciferase activity in cardiac muscle removed from rats with surgically induced cardiac hypertrophy. The authors reported greatly increased GATA4 DNA binding to the AGTR1 promoter in hypertrophied myocardium. These effects were abolished by the introduction of a mutation into the GATA consensus sequence within the AGTR1 promoter.
Laitinen et al. (2000) examined the expression of GATA4 and GATA6 (601656) in human ovaries, human granulosa-luteal (GL) cells, and sex cord-derived tumors. They showed by in situ hybridization and immunohistochemistry that GATA4 and GATA6 mRNA and GATA4 protein are present in granulosa and theca cells in both preantral and antral follicles. Both human ovarian tissue samples and freshly isolated GL cells derived from preovulatory follicles of gonadotropin-treated women expressed GATA4, GATA6, and FOG2 (603693) transcripts, and GATA6 mRNA expression in GL cell cultures was stimulated by human CG (see 118860) and 8-bromo-cAMP. The vast majority of granulosa and theca cell tumors examined expressed GATA4 and GATA6. They also found that mRNA for FOG2, a regulator of GATA4, is coexpressed with GATA4 in human ovary samples, normal granulosa cells, and in sex cord-derived tumors. The authors concluded that their findings support a role for GATA-binding proteins in human ovarian folliculogenesis. Moreover, they suggested that GATA factors may contribute to the phenotypes of sex cord-derived ovarian tumors.
Vaskivuo et al. (2001) investigated the extent and localization of apoptosis in human fetal (aged 13 to 40 weeks) and adult ovaries. They also studied the expression of transcription factor GATA4. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14 and 28, decreasing thereafter toward term. During fetal ovarian development, GATA4 mRNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. The authors concluded that the expression pattern of GATA4 suggests that it may be involved in the mechanisms protecting granulosa cells from apoptosis from fetal to adult life.
Anttonen et al. (2005) studied the role of factors regulating normal granulosa cell function, i.e., anti-mullerian hormone (AMH; 600957), inhibin-alpha (147380), steroidogenic factor-1 (SF1; 184757), and GATA transcription factors in the pathobiology and clinical behavior of granulosa cell tumors (GCTs). The more aggressive GCTs retained a high GATA4 expression, whereas the larger tumors lost the proliferation-suppressing AMH expression. The authors concluded that the high GATA4 expression in GCTs may serve as a marker of poor prognosis.
Ketola et al. (2000) found that GATA4 is expressed from early human fetal testicular development to adulthood. This transcription factor is evident in Sertoli cells through fetal and postnatal development. Expression of GATA4 in Sertoli cells peaks at 19 to 22 weeks' gestation, at the time of high circulating fetal FSH (see 136530). In Leydig cells, GATA4 is expressed during the fetal period and after puberty, coinciding with the periods of active androgen synthesis in the testis; this suggests a link between GATA4 and steroidogenesis. Also, fetal germ cells and prepubertal spermatogonia express GATA4, and it is downregulated in these cells after puberty. In androgen resistance, GATA4 expression in Sertoli and germ cells is weak or totally absent. GATA4 protein is abundantly present in Sertoli and Leydig cell tumors, suggesting a relationship to tumorigenesis or tumor progression in somatic cell-derived testicular neoplasms.
The transcription factors Hnf3a (602294) and Gata4 are the earliest known to bind the albumin gene enhancer in liver precursor cells in mouse embryos. To determine how they access sites in silent chromatin, Cirillo et al. (2002) assembled nucleosome arrays containing albumin enhancer sequences and compacted them with linker histone. Hnf3a and Gata4, but not human NF1 (see 600727), mouse Cebp-beta (189965), or yeast GAL4-AH, bound their sites in compacted chromatin and opened the local nucleosomal domain in the absence of ATP-dependent enzymes. The authors showed that the ability of Hnf3a to open chromatin is mediated by a high-affinity DNA-binding site and by the C-terminal domain of the protein, which binds histones H3 and H4. They concluded that factors that potentiate transcription in development are inherently capable of initiating chromatin opening events.
Durocher et al. (1997) demonstrated that GATA4 and NKX2.5 (600584) specifically cooperate in activating atrial natriuretic factor (ANF; 108780) and other cardiac promoters, and physically interact both in vitro and in vivo. Garg et al. (2003) found that GATA4 interacts with TBX5 (601620) and raised the possibility that GATA4, NKX2.5, and TBX5 function in a complex to regulate a subset of genes required for cardiac septal formation.
Using rodent and cell culture models, Heineke et al. (2007) showed that Gata4 has a role in cardiac angiogenesis. Enhanced Gata4 activity increased myocardial capillary and small conducting vessel densities, coronary muscle perfusion reserve, and perfusion-dependent cardiac contractility. Gata4 also promoted pressure overload-induced angiogenesis. Gata4 upregulated expression of the angiogenic factor Vegf (192240) by directly binding the Vegf promoter and enhancing transcription. Pressure overload-induced dysfunction in Gata4-deleted hearts was partially rescued by overexpression of Vegf and angiopoietin-1 (ANGPT1; 601667).
Takeuchi and Bruneau (2009) defined the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. They showed that 2 cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodeling complexes, Baf60c (SMARCD3; 601737), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally noncardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 and Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of noncardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. Takeuchi and Bruneau (2009) concluded that the combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.
Kang et al. (2015) found that ectopic expression of GATA4 induces senescence while disruption of GATA4 suppresses it, thus establishing GATA4 as a senescence regulator. GATA4 protein abundance, but not mRNA, increased during senescence, primarily as a result of increased protein stability. Stabilized GATA4 induces TRAF3IP2 (607043) and IL1A (147760), which activate NF-kappa-B (see 164011) to initiate and maintain the senescence-associated secretory phenotype (SASP). GATA4 pathway activation depends on the key DNA damage response kinases ATM (607585) and ATR (601215) as well as the senescence-associated activation of p53 (191170) and p16INK4a (600160). However, the GATA4 pathway is independent of p53 and p16INK4a.
Donaghey et al. (2018) examined genomic occupancy of GATA4 at endogenously bound cis-regulatory elements across multiple human cell types and found that genomic occupancy of GATA4 was cell-type specific. A low level of GATA4 enrichment was found in all cells endogenously expressing GATA4. Analysis of immortalized foreskin fibroblasts, which do not endogenously express GATA4, showed that ectopic GATA4 expression did not lead to higher enrichment at most of the endogenous target sites, with little overlap between endogenous and ectopic GATA4 for most regions occupied by GATA4 in alternative cell lines. Low-level GATA4 enrichment was also a feature of cells ectopically expressing FOXA2. These results indicated that the preexisting epigenome must affect GATA4 binding. Further analysis revealed that cell type-specific binding was influenced by additional cofactors, as GATA4 coexpression increased FOXA2 (600288) enrichment at sites investigated.
Pehlivan et al. (1999) provided evidence that GATA4 may be involved in the etiology of some congenital heart defects. They performed FISH analysis using a GATA4 probe on 5 patients with interstitial deletions of 8p23.1. Hemizygosity for GATA4 was seen in the 4 patients with congenital heart disease but not in the patient without known cardiac anomalies. The authors proposed that haploinsufficiency of GATA4 may contribute to the congenital heart disease observed in some patients with del(8)(p23.1).
Kennedy et al. (2001) hypothesized that a severe congenital heart defect in a 16-year-old female was due to disruption of the GATA4 gene by a duplication at 8p23.1. The father also had the duplication and had a less severe congenital heart defect, possibly due to the fact that the duplication was in a mosaic form.
Garg et al. (2003) identified a G296S mutation (600576.0001) in GATA4 affecting all 16 individuals in 5 generations of a family with congenital heart defects. All affected individuals had atrial septal defects (607941), and 8 had additional forms of congenital heart defects, including ventricular septal defects (VSD), atrioventricular septal defects (AVSD), pulmonary valve thickening, or insufficiency of the cardiac valves. None had cardiac conduction or other organ defects. In a second 4-generation pedigree with autosomal dominant transmission, Garg et al. (2003) identified a frameshift at codon 359 (E359del; 600576.0002). Similar to the first family, neither the cardiac conduction system nor other organs were affected in this family. The G296S mutation affects a residue highly conserved across species and lies adjacent to the nuclear localization signal (NLS) at the carboxy-terminal zinc finger, whereas the E359del mutation results in truncation of the last 40 amino acids or possibly nonsense-mediated decay. In an overexpression system, the G296S mutation displayed less transcriptional activation of the alpha-myosin heavy chain (160710) and atrial natriuretic factor (ANF; 108780) enhancers compared to wildtype, suggesting mildly reduced activity. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of GATA4. Furthermore, the G296S mutation abrogated a physical interaction between GATA4 and TBX5 (601620), a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of GATA4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects.
Tomita-Mitchell et al. (2007) identified 4 missense sequence variants in the GATA4 gene (see, e.g., 600576.0004; 600576.0005) in 5 of 628 patients with cardiac septal or conotruncal defects. One patient had tetralogy of Fallot (187500). The findings indicated that GATA4 mutations are uncommon in patients with septal defects.
Rajagopal et al. (2007) analyzed the GATA4 gene in 107 patients with congenital heart defects in the spectrum of Gata4-mutant mice and identified heterozygous missense mutations in 4 patients, including 1 (12.5%) of 8 patients with ASD (G296C; 600576.0006), 2 (4.8%) of 43 patients with endocardial cushion defect (AVSD4, 614430; 600576.0007 and 600576.0008), and 1 (11.1%) of 9 patients with right ventricular hypoplasia (see 277200) in the context of doublet inlet left ventricle. No mutations were found in 48 patients with cardiomyopathy.
Zhang et al. (2008) analyzed the GATA4 gene in 486 Chinese patients with congenital heart defects and identified 9 heterozygous mutations in 12 patients, including 9 (2.8%) of 319 patients with ventricular septal defect (VSD1, 614429; see, e.g., 600576.0007 and 600576.0009-600576.0010), 2 (3.1%) of 64 patients with tetralogy of Fallot (600576.0011; 600576.0012) and 1 (9.1%) of 11 patients with endocardial cushion defect (600576.0007). None of the patients manifested a conduction defect.
Peng et al. (2010) screened 135 Chinese pediatric patients with nonfamilial congenital heart defects for mutations in GATA4 and identified 2 heterozygous missense mutations, including 1 in a patient with tetralogy of Fallot (600576.0007) and 1 in a patient with VSD (600576.0013).
Chen et al. (2010) identified a heterozygous missense mutation in the GATA4 gene (600576.0016) in affected members of a 3-generation Chinese family segregating autosomal dominant atrial septal defect and pulmonary stenosis. Analysis of GATA4 in 30 additional patients with nonsyndromic congenital heart defects, including 10 with ASD, 10 with VSD, 8 with VSD combined with ASD, and 2 with AVSD did not reveal any mutations.
In 8 affected members of a Chinese family with secundum ASD, Chen et al. (2010) identified a heterozygous missense mutation in GATA4 (600576.0017). No GATA4 mutations were found in 70 patients with sporadic congenital heart defects, including 20 with ASD.
Wang et al. (2011) scanned the GATA4 gene in 210 unrelated Chinese patients with VSD, 45 of whom had additional cardiac anomalies, and identified a heterozygous missense mutation (G296R; 600576.0014) in 1 proband (estimated population prevalence of GATA4 mutations, 0.48%). The authors noted that mutation at GATA4 codon 296 had been previously identified in patients with VSD and other cardiac anomalies (G296S; 600576.0001) and in a family with ASD and pulmonary stenosis (G296C; 600576.0006), indicating that gly296 is functionally important and a hotspot for mutation.
Yang et al. (2012) sequenced the coding exons and exon/intron boundaries of the GATA4 gene in 160 unrelated Han Chinese individuals with VSD, and identified a heterozygous missense mutation (R43W; 600576.0015) in 1 (0.63%) of the 160 patients that was not found in 200 ethnically matched controls.
In 2 brothers and their male cousin from a French family with testicular anomalies and congenital heart disease (615542), Lourenco et al. (2011) identified heterozygosity for a missense mutation in the GATA4 gene (G221R; 600576.0018). Functional analysis showed that the G221R mutant disrupted synergistic activation of the anti-mullerian hormone (AMH; 600957) promoter by GATA4 and NR5A1 (184757), and also failed to bind to FOG2 (ZFPM2; 603693), a protein partner essential for gonad formation. The authors suggested that the absence of associated gonadal anomalies in previously reported cases of congenital heart disease associated with GATA4 mutations might be due to the ability of the mutated GATA4 proteins to retain the ability to interact with either FOG2 or NR5A1, or both.
Somatic Mutations
In diseased cardiac tissues from 2 of 52 explanted hearts of unrelated patients with complex cardiac malformations, notably ventricular and atrioventricular septal defects, Reamon-Buettner and Borlak (2006) found 3 nonsynonymous mutations in the HEY2 gene (604674). Since the 2 AVSD patients also carried binding domain mutations in other cardiac-specific transcription factors, e.g., NKX2-5 (600584), TBX5 (601620), and GATA4, Reamon-Buettner and Borlak (2006) concluded that breakdown of combinatorial interactions of transcription factors may have contributed to the complexity of their cardiac malformations.
Crispino et al. (2001) created mice harboring a single amino acid replacement in Gata4 that impaired the ability of the protein to interact with Fog2. These mice died just after embryonic day 12.5 and exhibited features similar to Fog2-null embryos, most notably absence of coronary vasculature and reduced staining for Flk1 (191306) and intracellular adhesion molecule-2 (ICAM2; 146630). However, the Gata4 mutant mice also showed semilunar cardiac valve defects and a double-outlet right ventricle not seen in Fog2-null mice. Crispino et al. (2001) concluded that GATA4 function is dependent on interaction with FOG2 and likely with an additional cardiac-specific FOG protein.
Watt et al. (2004) found that Gata4-null mouse embryos displayed heart defects characterized by disrupted looping morphogenesis, septation, and a hypoplastic ventricular myocardium. Myocardial gene expression was relatively normal, and Gata4 expression in the endocardium was dispensable for trabeculae formation. The proepicardium was absent in Gata4-null embryos, blocking formation of the epicardium. Watt et al. (2004) concluded that the observed myocardial defects may be secondary to loss of the proepicardium and that GATA4 is essential for generation of the proepicardium.
Zeisberg et al. (2005) generated mice with conditional deletion of Gata4 at early and late time points in cardiac morphogenesis. Early deletion resulted in hearts with striking myocardial thinning, absence of mesenchymal cells within the endocardial cushions, and selective hypoplasia of the right ventricle. Right ventricular hypoplasia was associated with downregulation of Hand2 (602407), and cardiomyocyte proliferation was reduced to a greater extent in the right ventricle compared to the left. Late deletion of Gata4 resulted in marked myocardial thinning with decreased cardiomyocyte proliferation, as well as double-outlet right ventricle. Zeisberg et al. (2005) concluded that myocardial GATA4 has a general role in regulating cardiomyocyte proliferation and a specific, stage-dependent role in regulating the morphogenesis of the right ventricle and the atrioventricular canal.
Mice heterozygous for either a Gata4 or Gata6 (601656) null allele are normal; however, Xin et al. (2006) found that compound heterozygosity of Gata4 and Gata6 null alleles resulted in embryonic lethality by day 13.5, accompanied by a spectrum of cardiovascular defects. They concluded that the cardiovascular system is exquisitely sensitive to levels of GATA4 and GATA6 and suggested that these GATA factors act cooperatively in cardiovascular development.
Rajagopal et al. (2007) studied mice heterozygous for a Gata4 mutation that results in a 50% reduction of Gata4 protein levels, and observed atrial and ventricular septal defects, endocardial cushion defects (AVSD), right ventricular hypoplasia, and cardiomyopathy. The authors noted that genetic background strongly influenced the expression of AVSD and cardiomyopathy, indicating the presence of important genetic modifiers.
Qian and Bodmer (2009) utilized a Drosophila heart model involving mutation of pannier (pnr) to examine the function of GATA4 in adult heart physiology. Heterozygous pnr mutants had defective cardiac performance in response to electrical pacing of the heart as well as in elevated arrhythmias. Adult-specific disruption of pnr function using a dominant-negative form revealed a cardiac autonomous requirement of pnr in regulating heart physiology. Neuromancer (nmr), the Drosophila homolog of TBX20 (606061), was identified as a potential downstream mediator of pnr in regulating cardiac performance and rhythm regularity. Qian and Bodmer (2009) concluded that pnr is not only essential for early cardiac progenitor formation, along with tinman (NKX2-5; 600584) and T-box factors, but also plays an important role in establishing and/or maintaining proper heart function, which is partially through another key regulator, TBX20/nmr.
Using new genetic fate-mapping approaches, Kikuchi et al. (2010) identified a population of cardiomyocytes in zebrafish that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, Kikuchi et al. (2010) found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre recombinase-based lineage tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labeled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, Kikuchi et al. (2010) found that electrical conduction is reestablished between existing and regenerated cardiomyocytes between 2 and 4 weeks postinjury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signaling block led to gata4 expression and morphologic improvement of the injured ventricular wall without loss of scar tissue. Kikuchi et al. (2010) concluded that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocyte populations.
Huang et al. (2011) demonstrated the direct induction of functional hepatocyte-like (induced hepatocyte, iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1-alpha (142410), and Foxa3 (602295) and inactivation of p19(Arf) (600160). iHep cells showed typical epithelial morphology, expressed hepatic genes, and acquired hepatocyte functions. Notably, transplanted iHep cells repopulated the livers of fumarylacetoacetate hydrolase-deficient (Fah-null; see 613871) mice and rescued almost half of recipients from death by restoring liver functions.
In a 5-generation pedigree segregating autosomal dominant congenital heart defects, with all affected individuals manifesting atrial septal defect (607941), Garg et al. (2003) identified a G-to-A transition at nucleotide 886 of the GATA4 gene. This resulted in a gly-to-ser substitution at codon 296 (G296S). Eight of the 16 affected individuals had other congenital heart defects including ventricular septal defects, atrioventricular septal defects, pulmonary valve thickening, or insufficiency of cardiac valves. Neither the cardiac conduction system nor other organs were affected in this kindred. All affected individuals carried the mutation. None of the unaffected family members carried the mutation, nor was it identified in 3,000 unrelated individuals of diverse ethnicity.
In a 4-generation pedigree with 8 affected individuals with atrial septal defect (607941), Garg et al. (2003) identified a frameshift due to a single-nucleotide deletion associated with glutamic acid at residue 359, which they referred to as E359del. This mutation was identified in all affected family members and was not seen in any unaffected family members nor in 300 other control individuals.
In affected members of a 4-generation family with atrial septal defect, Hirayama-Yamada et al. (2005) identified a deletion (1075delG) in exon 5 of the GATA4 gene, resulting in a frameshift and premature termination at codon 359. A deceased member of the family, said to have dextrocardia rather than ASD, was found to have had the same mutation.
In affected members of a family with atrial septal defect (607941), Hirayama-Yamada et al. (2005) identified a 155C-T transition in exon 1 of the GATA4 gene, predicted to result in a ser52-to-phe (S52F) substitution in the transcriptional activation domain-1.
In a patient with atrial septal defect (607941), Tomita-Mitchell et al. (2007) identified a heterozygous 946C-G transversion in exon 4 of the GATA4 gene, resulting in a gln316-to-glu (Q316E) substitution in the nuclear localization signal of the protein. The patient also had small muscular ventricular septal defects and mild pulmonary valve stenosis, as well as noncardiac anomalies including developmental delay and hydrocephalus. The mutation was not identified in 159 control individuals.
In a patient with atrial septal defect (607941), Tomita-Mitchell et al. (2007) identified a heterozygous 1273G-A transition in the GATA4 gene, resulting in an asp425-to-asn (D425N) substitution. The patient's unaffected mother carried the mutation, suggesting incomplete penetrance. The mutation was also identified in an unrelated patient with tetralogy of Fallot (187500), who had a vague family history of congenital heart defects. The mutation was not identified in 264 control individuals.
Lek et al. (2016) reported that the D425N variant has a maximum population frequency of 0.0137 in the South Asian population, calling into question, but not refuting, the disease gene association.
In a proband with a secundum atrial septal defect (ASD2; 607941) and pulmonary stenosis, Rajagopal et al. (2007) identified heterozygosity for an 886G-T transversion in the GATA4 gene, resulting in a gly296-to-cys (G296C) substitution at a highly conserved residue in the C-terminal domain. The mutation was not found in 500 control chromosomes, 246 of which were ethnically matched. The proband's father, who had persistent left superior vena cava to coronary sinus connection, was found to carry the mutation. The proband also had a sister with secundum ASD, but her DNA was unavailable for testing.
In a proband with endocardial cushion defect (AVSD4; 614430) consisting of primum atrial septal defect and cleft mitral valve, Rajagopal et al. (2007) identified heterozygosity for a 487C-T transition in the GATA4 gene, resulting in a pro163-to-ser (P163S) substitution at a conserved residue in the TAD2 domain. The proband's father, who also carried the P163S mutation, was reportedly unaffected. The mutation was not found in 600 control chromosomes, 346 of which were ethnically matched.
In a 1-year-old Han Chinese girl with a Rastelli type A endocardial cushion defect and a 5-month-old Han Chinese male infant with an infracristal ventricular septal defect (VSD1; 614429), Zhang et al. (2008) identified heterozygosity for the GATA4 P163S substitution. The mutation was not found in 486 ethnically matched controls.
In a pediatric Chinese patient with tetralogy of Fallot (187500), Peng et al. (2010) identified heterozygosity for the P163S mutation in the GATA4 gene. The mutation was not found in 114 controls.
In a proband with endocardial cushion defect (AVSD4; 614430) consisting of primum atrial septal defect and cleft mitral valve, Rajagopal et al. (2007) identified heterozygosity for a 1037C-T transition in the GATA4 gene, resulting in an ala346-to-val (A346V) substitution at a relatively conserved residue in the C-terminal domain. The proband's mother, who also carried the mutation, was reportedly unaffected. The mutation was not found in 600 control chromosomes, 346 of which were ethnically matched.
In a 22-year-old Han Chinese mother and her 10-month-old daughter with ventricular septal defect (VSD1; 614429), Zhang et al. (2008) identified heterozygosity for a 1075G-A transition in exon 6 of the GATA4 gene, resulting in a glu359-to-lys (E359K) substitution at a highly conserved residue in the C terminus. The mutation was not found in 11 unaffected family members or in 486 ethnically matched controls. The mother and daughter each had undergone surgical repair of a paramembranous defect, measuring 12 mm and 15 mm, respectively, with a left-to-right shunt. The deceased maternal grandmother also had nonsyndromic VSD.
In 2 unrelated Han Chinese infants, a 3-month-old girl and a 6-month-old boy, with ventricular septal defect (VSD1; 614429), Zhang et al. (2008) identified heterozygosity for a 1325C-T transition in exon 7 of the GATA4 gene, resulting in an ala442-to-val (A442V) substitution at a highly conserved residue in the C terminus. The mutation was not found in 486 ethnically matched controls. Both patients had a 12- to 13-mm paramembranous defect, with a left-to-right shunt.
In a 3-month-old Han Chinese male infant with tetralogy of Fallot (187500), Zhang et al. (2008) identified heterozygosity for a 1220C-A transversion in the GATA4 gene, resulting in a pro407-to-gln (P407Q) substitution at a highly conserved residue.
In an 11-year-old Han Chinese boy with tetralogy of Fallot (187500), Zhang et al. (2008) identified heterozygosity for a 3-bp insertion (354insGCC) in the GATA4 gene, resulting in the insertion of an alanine residue (118_119insA) in the highly conserved first poly-alanine region.
In a Chinese pediatric patient with ventricular septal defect (VSD1; 614429), Peng et al. (2010) identified heterozygosity for a 1220C-A transversion in exon 6 of the GATA4 gene, resulting in a pro407-to-gln (P407Q) substitution in the C-terminal domain. The mutation was not found in 114 controls.
In a 5-year-old Chinese girl with ventricular septal defect (VSD1; 614429), Wang et al. (2011) identified heterozygosity for a 886G-C transversion in the GATA4 gene, resulting in a gly296-to-arg (G296R) substitution at a highly conserved residue. Her affected father and paternal aunt also carried the mutation; none of the 3 had atrioventricular conduction defects. Her father had atrial septal defect (ASD) in addition to VSD, and her deceased paternal grandfather had ASD, pulmonary stenosis, and atrioventricular block. The mutation was not found in 200 ethnically matched controls. Transfection studies in COS-7 cells with the G296R mutant demonstrated significantly reduced activation of a direct cardiac downstream target gene, ANP (NPPA; 108780), compared to wildtype GATA4.
In 7 affected members of a 3-generation Han Chinese family with ventricular septal defect (VSD1; 614429), Yang et al. (2012) identified heterozygosity for a 127C-T transition in the GATA4 gene, resulting in an arg43-to-trp (R43W) substitution at a highly conserved residue. All affected individuals had perimembranous VSD; additional cardiac structural defects were present in 3 of the mutation-positive patients, including atrial septal defect (ASD) in the proband's father and paternal grandfather and patent ductus arteriosus in her paternal aunt. A deceased paternal great uncle had VSD, ASD, and pulmonary artery stenosis. The mutation was not found in unaffected family members or in 200 ethnically matched controls. Functional analysis in transfected COS-7 cells demonstrated significantly reduced activation of the ANP (NPPA; 108780) promoter with the R43W mutant compared to wildtype GATA4.
In an affected father, 2 sons, and grandson from a Chinese family with atrial septal defect (ASD2; 607941) and pulmonary stenosis, Chen et al. (2010) identified heterozygosity for an 839C-T transition in exon 4 of the GATA4 gene, resulting in a thr280-to-met (T280M) substitution at a highly conserved residue in the C-terminal zinc finger. The mutation was not found in unaffected family members or in 800 controls.
In 4 affected sisters and 4 affected offspring from a Chinese family with secundum atrial septal defect (ASD2; 607941), Chen et al. (2010) identified heterozygosity for a 928A-G transition in exon 5 of the GATA4 gene, resulting in a met310-to-val (M310V) substitution in the conserved NLS domain. The mutation was also identified in the sisters' unaffected father, but was not found in other unaffected family members or in 100 controls. Three of the 8 affected individuals also had pulmonary stenosis.
In 2 brothers and their male cousin from a French family with testicular anomalies and congenital heart disease (615542), Lourenco et al. (2011) identified heterozygosity for a c.661G-A transition in the GATA4 gene, resulting in a gly221-to-arg (G221R) substitution at a highly conserved residue in the N-terminal zinc finger domain. The mutation was also found in their apparently unaffected mothers; DNA samples from other family members were not available. The mutation was not found in 450 European controls, including 342 of French ancestry. Functional analysis demonstrated that although the G221R protein localized to the nucleus, it lacked DNA-binding activity and showed severely impaired transactivation of the AMH (600957) promoter compared to wildtype. Although the mutant retained its ability to physically interact with NR5A1 (184757), it failed to synergize with NR5A1 to activate the AMH promoter. In addition, the G221R mutant failed to physically bind to a known protein cofactor, FOG2 (ZFPM2; 603693).
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