HGNC Approved Gene Symbol: GATA6
SNOMEDCT: 61959006, 722206009, 787779000, 86299006; ICD10CM: Q20.0, Q21.3; ICD9CM: 745.0, 745.2;
Cytogenetic location: 18q11.2 Genomic coordinates (GRCh38) : 18:22,169,589-22,202,528 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q11.2 | Atrial septal defect 9 | 614475 | Autosomal dominant | 3 |
| Atrioventricular septal defect 5 | 614474 | Autosomal dominant | 3 | |
| Pancreatic agenesis and congenital heart defects | 600001 | Autosomal dominant | 3 | |
| Persistent truncus arteriosus | 217095 | 3 | ||
| Tetralogy of Fallot | 187500 | Autosomal dominant | 3 |
GATA factors constitute a family of transcriptional regulatory proteins expressed with distinct developmental and tissue-specific profiles and are thought to regulate cell-restricted programs of gene expression. Suzuki et al. (1996) described the molecular cloning, chromosomal location, and the transcription of the human GATA6 gene. The cDNA encodes a predicted 449-amino acid protein that is highly conserved among vertebrates and includes 2 adjacent zinc finger/basic domains characteristic of the GATA factor family. The gene is transcribed in a pattern overlapping that of GATA4 (600576). Transcripts for both of these genes are prominent in heart, pancreas, and ovary, but only GATA6 mRNA was found in lung and liver. GATA6 transcripts were also detected in cultures of human and rat vascular smooth muscle cells. In these cells, GATA6 transcripts were downregulated when quiescent cultures were stimulated to proliferate in response to mitogen activation. The results demonstrate that GATA6 is subject to both tissue-specific and mitogen-responsive regulatory signals. Suzuki et al. (1996) commented that GATA6 is a prime candidate for a gene that regulates the differentiative state of vascular smooth muscle cells.
Maitra et al. (2010) performed in situ hybridization in wildtype mouse embryos at embryonic day 13.5 and observed higher levels of expression of GATA6 in the atrial and ventricular myocardium than in the atrioventricular valve leaflets. The highest levels of GATA6 expression were seen in the smooth muscle cells of the aorta and pulmonary artery, whereas lower levels were detectable in pulmonary valve leaflets.
By fluorescence in situ hybridization, Suzuki et al. (1996) mapped the GATA6 gene to 18q11.1-q11.2.
Laitinen et al. (2000) examined the expression of GATA4 and GATA6 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.
Ketola et al. (2003) studied GATA6 expression in human fetal testis using in situ hybridization and immunohistochemistry and compared these results with the expression of the apoptosis-related proteins BCL2 (151430) and BAX (600040). Apoptotic cells were scanty between weeks 16 and 40, and proliferation ceased during the third trimester, supporting the view that little tissue remodeling occurs in the late fetal testis. The authors concluded that despite strong expression, GATA6 did not correlate with apoptosis or cell proliferation and is therefore unlikely to be directly involved in these processes in the human fetal testis.
Ho et al. (2005) studied why GATA6 mRNA levels are increased in polycystic ovary syndrome (PCOS; 184700) theca cells. By quantitative RT-PCR analysis, they showed that nascent GATA6 transcript levels, which reflect GATA6 gene transcription, were significantly increased in PCOS theca cells. In normal theca cells, GATA6 mRNA had a short half-life, which was attributed to an AU-rich 3-prime untranslated region sequence; in PCOS theca cells, the half-life of GATA6 transcripts was significantly longer. Ho et al. (2005) identified no sequence variations in the GATA6 gene that were associated with PCOS.
Kamnasaran et al. (2007) identified Gata6 as a tumor suppressor by screening for genetic modifiers that accelerated transformation in a mouse malignant astrocytoma model. Loss of Gata6 resulted in enhanced proliferation and transformation of astrocytes. Human malignant astrocytoma cell lines, explant xenografts, and operative specimens demonstrated loss of GATA6 expression. Loss-of-function GATA6 mutations with loss of heterozygosity at the GATA6 locus were found in human malignant astrocytoma specimens, but not in lower grade astrocytomas or normal adult astrocytes. Knockdown of GATA6 expression led to accelerated tumorigenesis in p53 -/- mouse astrocytes and in human astrocytes expressing activated HRAS (190020). Conversely, elevated GATA6 expression in human malignant astrocytoma cells reduced their tumorigenic growth and decreased VEGF (192240) expression.
In a transgenic mouse system, Kodo et al. (2009) observed that mutation of conserved GATA consensus sites on enhancer elements of the downstream target genes Sema3c (602645) and Plxna2 (601054) abolished their activity in the cardiac outflow tract (OFT) and subpulmonary myocardium, and in cardiac neural crest derivatives in the OFT region, respectively. Kodo et al. (2009) concluded that there is direct regulation of SEMA3C and PLXNA2 expression through binding of GATA transcription factors, including GATA6.
Rosas et al. (2014) determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Rosas et al. (2014) concluded that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of proliferation renewal.
Kodo et al. (2009) screened the genomes of 21 unrelated Japanese patients with nonsyndromic persistent truncus arteriosus (PTA; see 217095) and identified heterozygosity for a 2-bp deletion (601656.0001) and a missense mutation (601656.0002) in the GATA6 gene, respectively, in 2 probands. The deletion segregated with congenital heart disease in the family of the first proband, whereas the second proband's mutation was de novo. Neither was found in 182 Japanese controls. In vitro analysis demonstrated that the mutants were unable to activate the GATA6-dependent cardiac promoters NPPA (108780), WNT2 (147870), SEMA3C (602645), and PLXNA2 (601054), and there was reduced binding efficiency to the latter 2 promoters, suggesting that each of the GATA6 mutations disturbs semaphorin-plexin signaling to varying degrees, resulting in abnormal development of the cardiac outflow tract.
Maitra et al. (2010) sequenced all 7 exons of the GATA6 gene in 310 children with a spectrum of congenital heart defects, and identified heterozygosity for 2 different missense mutations at highly conserved residues (601656.0003 and 601656.0004, respectively) in 1 patient with isolated tetralogy of Fallot (TOF; 187500) and in 1 patient with atrioventricular septal defect (AVSD5; 614474).
Lin et al. (2010) analyzed the coding region and exon-intron boundaries of the GATA6 gene in 270 sporadic Chinese patients with congenital heart defects and identified a heterozygous missense mutation (S184N; 601656.0005) in 3 patients, 2 with atrial septal defect (ASD9; 614475) and 1 with tetralogy of Fallot.
Allen et al. (2012) performed exome sequencing in 2 unrelated patients with pancreatic agenesis and congenital heart defects (HDCA; 600001) and their unaffected parents and identified heterozygosity for a de novo mutation in the GATA6 gene (601656.0006 and 601656.0007) in each proband. Subsequent analysis of GATA6 in another 24 probands with pancreatic agenesis who were negative for mutation in the PTF1A (607194) and PDX1 (600733) genes revealed 12 mutations in 13 of the probands (see, e.g., 601656.0008-601656.0011). Allen et al. (2012) noted that 14 of the 15 mutation-positive patients had congenital heart defects in addition to pancreatic agenesis, and other malformations or abnormalities were common in these patients.
In an affected female member of a Japanese family with congenital heart defects and pancreatic agenesis who was negative for mutation in 8 other genes associated with pancreatic development and/or function, Yorifuji et al. (2012) analyzed the GATA6 gene and identified heterozygosity for a 2-bp deletion (601656.0012). The authors noted that unlike previously reported patients with pancreatic agenesis and congenital heart defects, in whom de novo mutations caused complete agenesis or pronounced hypoplasia of the pancreas, the dominantly inherited mutation in this family resulted in a variable degree of pancreatic hypoplasia, severity of diabetes, and types of congenital cardiac defects present among the affected members of this family. Yorifuji et al. (2012) concluded that this observation broadened the clinical spectrum of diabetes caused by GATA6 haploinsufficiency, and that intrafamilial variability in phenotypic expression is relevant to the genetic counseling of such families.
In 5 affected individuals from 3 unrelated families with congenital diaphragmatic hernia and cardiac defects, Yu et al. (2014) identified heterozygosity for mutations in the GATA6 gene (see 601656.0008 and 601656.0013-601656.0014). There was no evidence for hyperglycemia or pancreatic insufficiency in any of the patients.
Morrisey et al. (1998) generated mice deficient in GATA6 by targeted disruption. Differentiated embryoid bodies derived from GATA6 -/- embryonic stem (ES) cells lacked a covering layer of visceral endoderm and severely attenuated, or failed to express, genes encoding early and late endodermal markers, including HNF4 (600281), GATA4, alpha-fetoprotein (AFP; 104150), and HNF3-beta (600288). Homozygous GATA6 -/- mice died between embryonic days 6.5 and 7.5 and exhibited a specific defect in endoderm differentiation, including severely downregulated expression of GATA4 and the absence of HNF4 gene expression. Moreover, widespread programmed cell death was observed within the embryonic ectoderm of GATA6-deficient embryos, a finding also observed in HNF4-deficient embryos. Consistent with these data, forced expression of GATA6 activated the HNF4 promoter in nonendodermal cells. Finally, to examine the function of GATA6 during later embryonic development, Morrisey et al. (1998) generated GATA6-deficient-_C57BL/6 chimeric mice. LacZ-tagged GATA6 -/- ES cells contributed to all embryonic tissues, with the exception of the endodermally derived bronchial epithelium. Morrisey et al. (1998) suggested that their data supports a model in which GATA6 lies upstream of HNF4 in a transcriptional cascade that regulates differentiation of the visceral endoderm. They concluded that GATA6 is required for establishment of the endodermally derived bronchial epithelium.
Lepore et al. (2006) found that targeted inactivation of the mouse Gata6 gene in vascular smooth muscle cells or in neural crest resulted in perinatal mortality from a spectrum of cardiovascular defects, including interrupted aortic arch and persistent truncus arteriosus. The defects did not result from impaired smooth muscle cell differentiation but rather were associated with attenuated expression of semaphorin-3C (SEMA3C; 602645). Lepore et al. (2006) concluded that the primary function of GATA6 during cardiovascular development is to regulate morphogenetic patterning of the cardiac outflow tract and aortic arch.
Mice heterozygous for either a Gata4 or Gata6 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.
In a Japanese female patient with persistent truncus arteriosus (PTA; see 217095), Kodo et al. (2009) identified heterozygosity for a 2-bp deletion in exon 5 of the GATA6 gene (1456delGA), causing a frameshift predicted to disrupt the nuclear localization signal and result in a premature termination codon that truncates 100 amino acids at the C terminus. Transfection studies with immunostaining showed an abnormal nuclear localization pattern with the mutant compared to wildtype, and cotransfection luciferase assays demonstrated loss of transcription activation of GATA6-dependent cardiac promoters. In addition, the mutant protein showed dominant-negative interaction with wildtype GATA6. The deletion was also present in heterozygosity in the proband's sister and father, both of whom had pulmonary stenosis. The sister also had patent ductus arteriosus and atrial septal defect, and atrial septal defect was also present in the proband. The mutation was not found in the unaffected mother or in 182 Japanese controls.
In a Japanese male patient with persistent truncus arteriosus (PTA; see 217095), Kodo et al. (2009) identified heterozygosity for a de novo 1396A-C transversion in exon 4 of the GATA6 gene, resulting in an asn466-to-his (N466H) substitution in the zinc finger. Cotransfection luciferase assays demonstrated loss of transcription activation of GATA6-dependent cardiac promoters. The mutation was not found in 182 Japanese controls.
In a Hispanic patient with tetralogy of Fallot (TOF; 187500), Maitra et al. (2010) identified heterozygosity for a 799C-G transversion in the GATA6 gene, resulting in a leu198-to-val (L198V) substitution at a highly conserved residue. The patient had a single malalignment ventricular septal defect with subvalvar/valvar pulmonary stenosis and a normal aortic arch. The mutation was also detected in the patient's unaffected mother, but was not found in 288 control individuals, including 96 of Hispanic ethnicity.
In a Hispanic patient with atrioventricular septal defect (AVSD5; 614474), Maitra et al. (2010) identified heterozygosity for a 740C-T transition in the GATA6 gene, resulting in an ala178-to-val (A178V) substitution at a highly conserved residue. No DNA was available from family members, but the mutation was not found in 288 control individuals, including 96 of Hispanic ethnicity. The patient had unbalanced AVSD, hypoplastic left ventricle, and 2 muscular ventricular septal defects with no additional evidence of heterotaxy syndrome (see 306955). Transfection studies demonstrated gain of function, with a 2-fold increase in transactivation ability with the mutant compared to wildtype.
In 3 sporadic Chinese patients with congenital heart defects, 2 with atrial septal defect (ASD9; 614475) and 1 with tetralogy of Fallot (TOF; 187500), Lin et al. (2010) identified heterozygosity for a 551G-A transition in exon 2 of the GATA6 gene, resulting in a ser184-to-asn (S184N) substitution at a highly conserved residue in the transcriptional activation domain. Functional analysis in HEK293 cells, using a direct cardiac downstream target, ANF (108780), as a luciferase reporter, demonstrated significantly decreased transcriptional activity and loss of dosage sensitivity for the mutant compared to wildtype. Studies in H9c2 rat cardiomyoblast cells using RT-PCR also showed impaired transcriptional ability of S184N GATA6. One of the ASD patients was a 3-year-old girl with an ostium secundum ASD and mild pulmonary arterial hypertension, whereas the other was a 4-year-old boy with an ostium secundum ASD and mild tricuspid valve disease and pulmonary valve replacement. The third patient was a 7-month-old boy with an overriding aorta (50% override), pulmonary stenosis, ventricular septal defect, and right atrial and ventricular hypertrophy. None of the patients had any other abnormalities. The S184N mutation was detected in the unaffected fathers of the boy with TOF and the girl with ASD, and it was also detected in the clinically unaffected mother of the boy with ASD, who was found to have bicuspid aortic valve on echocardiography. The mutation was not found in 500 ethnically matched controls.
In a patient with pancreatic agenesis and congenital heart defects (HDCA; 600001), Allen et al. (2012) identified heterozygosity for a de novo 1354A-G transition in exon 4 of the GATA6 gene, resulting in a thr452-to-ala (T452A) substitution on the DNA binding surface. The mutation was not present in the proband's unaffected parents or in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, the patient had atrial septal defect, developmental delay, and colonic perforation.
In a patient with pancreatic agenesis and congenital heart defects (600001), Allen et al. (2012) identified heterozygosity for a de novo 8-bp deletion in exon 5 of the GATA6 gene, predicted to cause a frameshift and premature termination codon. The mutation was not present in the proband's unaffected parents or in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, the patient had multiple ventricular septal defects, atrial septal defect, mild hypoplasia of right ventricle and tricuspid valve, pulmonary stenosis, patent ductus arteriosus, and gallbladder agenesis.
In 2 patients with pancreatic agenesis and congenital heart defects (600001), Allen et al. (2012) identified heterozygosity for a de novo 1366C-T transition in exon 4 of the GATA6 gene, resulting in an arg456-to-cys (R456C) substitution on the DNA binding surface. Electrophoretic mobility shift assay showed that the mutation abolishes binding to a predicted GATA6 binding sequence in the pancreatic HNF4A (600281) proximal promoter. The mutation was not present in the probands' unaffected parents or in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, 1 patient had truncus arteriosus, perimembranous ventricular septal defect, and developmental delay and seizures, whereas the other had tetralogy of Fallot, developmental delay, and umbilical hernia.
In a 3-year-old boy with tetralogy of Fallot, left diaphragmatic hernia, and a single umbilical artery, who had normal psychomotor development and no history of hyperglycemia, Yu et al. (2014) identified heterozygosity for the R456C mutation in the GATA6 gene. The mutation was not detected in the proband's unaffected parents or in 183 controls.
In a patient with pancreatic agenesis and congenital heart defects (600001), Allen et al. (2012) identified heterozygosity for a de novo 1367G-A transition in exon 4 of the GATA6 gene, resulting in an arg456-to-his (R456H) substitution on the DNA binding surface. Electrophoretic mobility shift assay showed that the mutation abolishes binding to a predicted GATA6 binding sequence in the pancreatic HNF4A (600281) proximal promoter. The mutation was not present in the proband's unaffected parents or in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, the patient had patent ductus arteriosus, ventricular septal defect, hypoplastic left pulmonary artery, and severe developmental delay.
In a patient with pancreatic agenesis and congenital heart defects (600001), Allen et al. (2012) identified heterozygosity for a 1396A-G transition in exon 4 of the GATA6 gene, resulting in an asn466-to-asp (N466D) substitution on the DNA binding surface. Electrophoretic mobility shift assay showed that the mutation abolishes binding to a predicted GATA6 binding sequence in the pancreatic HNF4A (600281) proximal promoter. DNA was not available from the proband's unaffected father, but the mutation was not found in the unaffected mother or in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, the patient had patent ductus arteriosus, transient hypothyroidism, gallbladder agenesis, developmental delay, epilepsy, and intestinal malrotation and microcolon.
In a patient with pancreatic agenesis and congenital heart defects (600001), Allen et al. (2012) identified heterozygosity for a 1399G-A transition in exon 4 of the GATA6 gene, resulting in an ala467-to-thr (A467T) substitution on the DNA binding surface. Electrophoretic mobility shift assay showed that the mutation abolishes binding to a predicted GATA6 binding sequence in the pancreatic HNF4A (600281) proximal promoter. DNA was not available from the proband's unaffected parents, but the mutation was not found in 1,094 population controls from the 1000 Genomes Project database. In addition to pancreatic agenesis, the patient had atrial septal defect and pulmonary stenosis, pituitary agenesis, and moderate learning difficulties and seizures.
In an affected female member of the Japanese family with pancreatic agenesis and congenital heart defects (HDCA; 600001) originally reported by Yorifuji et al. (1994), Yorifuji et al. (2012) identified heterozygosity for a 2-bp deletion (1504delAA) in exon 4 of the GATA6 gene, predicted to affect the DNA-binding capacity of the mutant protein. Yorifuji et al. (2012) noted that affected members of this family had a variable degree of pancreatic hypoplasia and severity of diabetes ranging from neonatally lethal diabetes with only a remnant of pancreatic tissue to adult-onset diabetes associated with dorsal agenesis of the pancreas. Similar intrafamilial variability was observed with regard to the types of congenital heart defects present in affected individuals.
In a male infant with a large ventricular septal defect (VSD) and diaphragmatic hernia (HDCA; 600001), Yu et al. (2014) identified heterozygosity for a c.712G-T transversion in the GATA6 gene, resulting in a gly238-to-ter (G238X) substitution that was not found in 183 controls. Sanger sequencing confirmed that the mutation occurred de novo in his affected mother, who had patent ductus arteriosus, congenital absence of the pericardium, and intestinal malrotation. Quantitative analysis of blood- and saliva-derived DNA from the mother revealed somatic mosaicism consistent with her significantly milder phenotype: only 16% of alleles from saliva and 15% from blood were mutant, suggesting that the mutation was postzygotic. The G238X mutation was also detected in an aborted female fetus from the mother's second pregnancy; autopsy revealed left diaphragmatic hernia, large VSD, bilateral cervical ribs, absent right twelfth rib, and left ureteral duplication. In addition, although pancreatic tissue was identified in the fetus, it was noted to be ectopically located, in association with the mesentery of the small bowel.
In a patient with atrial septal defect and diaphragmatic hernia (HDCA; 600001), Yu et al. (2014) identified heterozygosity for a de novo 1-bp deletion (c.1071delG) in the GATA6 gene, causing a frameshift predicted to result in a premature termination codon (Val358Cysfs34Ter). The mutation was not present in the unaffected parents, in 183 controls, or in the 1000 Genomes Project or Exome Variant Server databases.
Allen, H. L., Flanagan, S. E., Shaw-Smith, C., De Franco, E., Akerman, I., Caswell, R., International Pancreatic Agenesis Consortium, Ferrer, J., Hattersley, A. T., Ellard, S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nature Genet. 44: 20-22, 2012. [PubMed: 22158542] [Full Text: https://doi.org/10.1038/ng.1035]
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Kamnasaran, D., Qian, B., Hawkins, C., Stanford, W. L., Guha, A. GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model. Proc. Nat. Acad. Sci. 104: 8053-8058, 2007. [PubMed: 17463088] [Full Text: https://doi.org/10.1073/pnas.0611669104]
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Suzuki, E., Evans, T., Lowry, J., Truong, L., Bell, D. W., Testa, J. R., Walsh, K. The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals. Genomics 38: 283-290, 1996. [PubMed: 8975704] [Full Text: https://doi.org/10.1006/geno.1996.0630]
Xin, M., Davis, C. A., Molkentin, J. D., Lien, C.-L., Duncan, S. A., Richardson, J. A., Olson, E. N. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc. Nat. Acad. Sci. 103: 11189-11194, 2006. [PubMed: 16847256] [Full Text: https://doi.org/10.1073/pnas.0604604103]
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Yorifuji, T., Matsumura, M., Okuno, T., Shimizu, K., Sonomura, T., Muroi, J., Kuno, C., Takahashi, Y., Okuno, T. Hereditary pancreatic hypoplasia, diabetes mellitus, and congenital heart disease: a new syndrome? J. Med. Genet. 31: 331-333, 1994. [PubMed: 8071961] [Full Text: https://doi.org/10.1136/jmg.31.4.331]
Yu, L., Bennett, J. T., Wynn, J., Carvill, G. L., Cheung, Y. H., Shen, Y., Mychaliska, G. B., Azarow, K. S., Crombleholme, T. M., Chung, D. H., Potoka, D., Warner, B. W., and 9 others. Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia. J. Med. Genet. 51: 197-202, 2014. [PubMed: 24385578] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101989]