HGNC Approved Gene Symbol: GATA2
SNOMEDCT: 700057001, 778024005;
Cytogenetic location: 3q21.3 Genomic coordinates (GRCh38): 3:128,479,422-128,493,201 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3 | {Leukemia, acute myeloid, susceptibility to} | 601626 | Autosomal dominant; Somatic mutation | 3 |
| {Myelodysplastic syndrome, susceptibility to} | 614286 | 3 | ||
| Emberger syndrome | 614038 | Autosomal dominant | 3 | |
| Immunodeficiency 21 | 614172 | Autosomal dominant | 3 |
The GATA family of transcription factors, which contain zinc fingers in their DNA binding domain, have emerged as candidate regulators of gene expression in hematopoietic cells (Tsai et al., 1994). GATA1 (305371) is essential for normal primitive and definitive erythropoiesis and is expressed at high levels in erythroid cells, mast cells, and megakaryocytes. GATA2 is expressed in hematopoietic progenitors, including early erythroid cells, mast cells, and megakaryocytes, and also in nonhematopoietic embryonic stem cells. In chicken erythroid progenitors, forced expression of GATA2 promotes proliferation at the expense of differentiation (Briegel et al., 1993). GATA3 (131320) expression is restricted to T-lymphoid cells and some nonhematopoietic cell types, including embryonic stem cells.
GATA2 was cloned by Lee et al. (1991) by degenerate PCR from a human umbilical vein endothelial cell library. The predicted 480-amino acid protein was 6 residues longer than that predicted by the cDNA isolated by Dorfman et al. (1992). The human protein is similar to chicken GATA-2 (also called NF-E1b). The message is expressed in a variety of cell lines and tissue types.
Hsu et al. (2011) stated that the 480-amino acid GATA2 protein contains 2 zinc finger domains and a nuclear localization signal in its C-terminal half.
Hsu et al. (2011) reported that the GATA2 gene contains 7 exons. The two 5-prime exons are untranslated.
Ciciotte et al. (1997) mapped the mouse Gata2 gene to chromosome 6 by study of DNA from an interspecific backcross panel. They pointed out that the human gene had been mapped to chromosome 3 by Dorfman et al. (1992) using DNA from a panel of 12 rodent/human hybrids containing various human chromosomes and applying Southern blot analysis.
By exon trapping using a PAC contig spanning a breakpoint region associated with myeloid leukemia (see 601626), Wieser et al. (2000) mapped the GATA2 gene to chromosome 3q21. GATA2 is transcribed from telomere to centromere.
Dorfman et al. (1992) followed up on the previous observation that the promoter of the gene encoding preproendothelin-1 (EDN1; 131240) contains a GATA motif that is essential for activity and interacts with a nuclear factor similar in size and binding specificity to the erythroid transcription factor GATA1. Human homologs of other known GATA-binding transcription factors were either absent in endothelial cells (in the case of GATA1) or were made in small quantities and not significantly affected by retinoic acid in these cells (in the case of GATA3), making it unlikely that they regulate the EDN1 gene. Dorfman et al. (1992) proposed that GATA2 is the GATA-binding protein required for EDN1 gene expression in endothelial cells.
Tong et al. (2000) showed that murine GATA2 and GATA3 are specifically expressed in white adipocyte precursors and that their downregulation sets the stage for terminal differentiation. Constitutive GATA2 and GATA3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. This effect was mediated, at least in part, through the direct suppression of peroxisome proliferator-activated receptor-gamma (PPARG; 601487). GATA3-deficient embryonic stem cells exhibit an enhanced capacity to differentiate into adipocytes, and defective GATA2 and GATA3 expression is associated with obesity. Thus, Tong et al. (2000) concluded that GATA2 and GATA3 regulate adipocyte differentiation through molecular control of the preadipocyte-adipocyte transition.
Chun et al. (2003) demonstrated that GATA2 is covalently modified by SUMO1 (601912) and SUMO2 (603042) and that PIASY (605989), through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO2 to GATA2. PIASY suppressed GATA2-dependent ET1 promoter activity in bovine carotid endothelial cells. The suppressive effect of PIASY required the GATA-binding site in the ET1 promoter and depended upon the interaction between PIASY and GATA2.
Pimanda et al. (2007) identified Gata2, Tal1 (187040), and Fli1 (193067) and their enhancers as components of a gene regulatory network that operates during specification of mouse hematopoietic stem cells in the aorta-gonad-mesonephrose region and in fetal liver at midgestation.
Mammoto et al. (2009) showed that the Rho inhibitor p190RhoGAP (GRLF1; 605277) controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between 2 antagonistic transcription factors, TFII-I (GTF2I; 601679) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (191306). Moreover, this angiogenesis signaling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. Mammoto et al. (2009) suggested that this finding represented the first known functional crossantagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.
Kazenwadel et al. (2012) found selective expression of the Gata2 gene in primary lymphatic cells, lymphatic vessels, and lymphatic vascular valves of embryonic and adult mouse tissues. Gata2 was not present in blood vascular endothelial cells or blood vessels. Knockdown of Gata2 in lymphatic endothelial cells isolated from the dermis of embryonic mice resulted in decreased expression of Gata2 target genes, including genes important for lymphatic vascular or valve maturation, such as Angpt2 (601922) and Prox1 (601546). The findings indicated that GATA2 has a role in lymphatic vascular development and/or function, which is consistent with the observation of lymphedema in some patients with loss-of-function GATA2 mutations (e.g., 137295.0009).
Brenner et al. (2015) identified 11 putative binding sites for GATA2, 4 for CEBPB (189965), and 2 for ZSCAN21 (601261) in the promoter region of the human alpha-synuclein gene (SNCA; 163890) Chromatin immunoprecipitation (ChIP) analysis and EMSA of human brain nuclear extracts confirmed highly specific binding of GATA2 to a specific region within SNCA intron 2, and of ZSCAN21 to a single region within SNCA intron 1.
Wieser et al. (2000) determined that most breakpoints at chromosome 3q21 associated with myeloid leukemia are located in the presumptive GATA2 regulatory region. They found that GATA2 was overexpressed in established leukemia cell lines and in 7 of 9 leukemia patient samples showing chromosome 3q21 aberrations.
Association with Early-Onset Coronary Artery Disease
Connelly et al. (2006) genotyped 2,260 affected and 603 unaffected individuals from 1,101 families with early-onset coronary artery disease (see 608901) for 17 SNPs in the GATA2 gene and found significant association with disease for 2 pairwise haplotypes (p = 0.001 after Bonferroni correction).
Association with Chronic Myeloid Leukemia
In bone marrow cells derived from 8 (9.41%) of 85 unrelated patients with chronic myeloid leukemia (608232) during blast crisis transformation, Zhang et al. (2008) identified heterozygosity for a somatic leu359-to-val (L359V) mutation in the GATA2 gene. This mutation was not present during the chronic phase of the disease. One additional patient with blast crisis and eosinophilia had an in-frame 18-bp deletion in the GATA2 gene. Both mutations were located within or close to the N terminus of the ZF2 domain, which is responsible for DNA binding, self-association, and heterodimerization. Neither mutation was detected in 200 healthy controls or in 233 patients with other forms of blood cancer. The patients with GATA2 mutations showed a poorer prognosis compared to other CML patients in blast crisis. Functional expression studies showed that the L359V mutation resulted in a gain-of-function effect with increased activity, whereas the deletion resulted in decreased activity. The L359V mutation also enhanced the inhibitory effects on the activity of PU.1 (SPI1; 165170), a major regulator of myelopoiesis. Transduction of the GATA2 L359V mutant into HL-60 cells or BCR/ABL-harboring murine cells disturbed myelomonocytic differentiation/proliferation in vitro and in vivo, respectively. These data strongly suggest that GATA2 mutations play a role in acute myeloid transformation in a subset of CML patients.
Immunodeficiency 21
Hsu et al. (2011) identified 12 distinct heterozygous mutations in the GATA2 gene in 20 patients with a primary immunodeficiency (IMD21; 614172) characterized by dendritic cell, monocyte, B lymphocyte, and natural killer (NK) lymphocyte deficiency. In 2 kindreds, the mutation identified in the proband was identified in an affected relative, confirming germline transmission. Five of the 6 missense mutations, including 2 recurrent mutations, arg398 to trp (R398W; 137295.0001) and thr354 to met (T354M; 137295.0002), affected the zinc finger-2 domain in GATA2, suggesting dominant interference of protein function. The remaining missense mutation, pro254 to leu (P254L; 137295.0003), occurred before the zinc fingers and was predicted to be damaging. Six patients had insertion/deletion mutations, 4 of which (e.g., 137295.0004) led to frameshifts and premature termination and implicated haploinsufficiency. Hsu et al. (2011) concluded that GATA2, like RUNX1 (151385) and CEBPA (116897), is involved in familial leukemia and in a complex congenital immunodeficiency that evolves over decades and leads to predisposition to infection and myeloid malignancy.
By exome sequence analysis of 4 unrelated patients with immunodeficiency previously reported by Bigley et al. (2011), including 3 with sporadic disease, Dickinson et al. (2011) found that only mutations in GATA2 were shared by all 4 patients. Each patient harbored a unique heterozygous mutation, but all were predicted to be deleterious. The mutations included 2 missense mutations within the zinc finger domain, R398W and T354M, a 1-bp insertion in codon 200 (137295.0007) predicted to cause a frameshift and premature termination, and a splice acceptor site mutation (137295.0008) predicted to cause skipping of exon 5 and a 42-amino acid deletion. The frameshift and splice acceptor mutations were expected to result in complete loss of the C-terminal zinc finger domain and to cause DCML through haploinsufficiency of GATA2.
Johnson et al. (2012) identified a woman of European descent who developed a constellation of conditions characteristic of IMD21 by the age of 27 years. The patient lacked mutations in her GATA2 cDNA, and 3 conserved GATA regulatory sites upstream of the GATA2 promoter were identical to wildtype. However, Johnson et al. (2012) identified a 28-bp deletion in intron 5 at +9.5 kb (137295.0015) that affected a conserved composite E-box/GATA element. The deletion excised an imperfect GATA motif (GATAG), the E-box of the conserved composite element (CATCTG), and 5 bp of the 8-bp spacer between the E-box and the GATA motif (AGATAA). Johnson et al. (2012) suggested that heterozygous mutation of the +9.5 site reduces GATA2 expression in vivo.
Mace et al. (2013) found that the NK cells of 5 patients with immunodeficiency due to GATA2 mutations showed a profound defect in NK cell-mediated cytotoxicity, as well as a defect in antibody-mediated cellular toxicity. There was a severe reduction in CD56 (NCAM1; 116930)-bright cells, which represent the precursor NK-cell pool, and the remaining NK cells were CD56-dim, representing the mature pool. Analysis of control NK cells showed that GATA2 was expressed primarily in the CD56-bright pool, suggesting an important role for GATA2 in the differentiation, maturation, and survival of NK cells.
Primary Lymphedema with Myelodysplasia
Using whole-exome sequencing in 3 unrelated patients with Emberger syndrome (primary lymphedema with myelodysplasia; 614038), Ostergaard et al. (2011) identified heterozygosity for 3 different truncating mutations in the GATA2 gene (137295.0009-137295.0011). Sanger sequencing of GATA2 coding exons and splice sites in 5 additional unrelated probands revealed a heterozygous mutation in each proband (see, e.g., 137295.0012 and 138295.0013). Six of the 8 mutations were predicted to cause premature termination of the protein; the 2 missense mutations that were identified involved conserved residues, and functional analysis demonstrated significant reduction of GATA2 transactivation activity in vitro.
Association with Predisposition to Myelodysplastic Syndrome and Acute Myeloid Leukemia
Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a predisposition to myelodysplastic syndrome (MDS; 614286) and acute myeloid leukemia (AML; 601626). In 3 of the families they identified a heritable heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002) that segregated with disease and was not found in 695 nonleukemic ethnically matched controls. In another family, they identified a 3-bp deletion in GATA2 (137295.0014) in a father and son with MDS.
By gene targeting in mouse embryonic stem cells, Tsai et al. (1994) demonstrated that the transcription factor GATA2 plays a critical role in hematopoiesis. Primitive hematopoiesis in the yolk sac of mutant mice was greatly reduced and led to severe anemia and death. Definitive hematopoiesis, evident in fetal liver followed by maintenance in the spleen and then adult bone marrow, was also significantly affected (greater than 50-fold). These data are most consistent with GATA2 serving as a regulator of genes controlling growth factor responsiveness or proliferative capacity of early hematopoietic cells.
Mutations resulting in embryonic or early postnatal lethality could mask the activities of any gene in unrelated and temporally distinct developmental pathways. Targeted inactivation of GATA2 leads to midgestational death as a consequence of hematopoietic failure. Zhou et al. (1998) showed that a 250-kb GATA2 YAC is expressed strongly in both the primitive and definitive hematopoietic compartments, while 2 smaller YACs are not. This largest YAC also rescues hematopoiesis in vitro and in vivo, thereby localizing the hematopoietic regulatory cis element(s) between 100 and 150 kb 5-prime to the GATA2 structural gene. Introducing the YAC transgene into the GATA2 -/- genetic background allowed the embryos to complete gestation; however, newborn rescued pups quickly succumbed to lethal hydroureter nephrosis, and displayed a complex array of genitourinary abnormalities. These findings demonstrated that GATA2 plays equally vital roles in urogenital and hematopoietic development.
Using transgenic mice expressing the pituitary-specific transcription factor-1 (PIT1; 173110) and/or GATA2 genes, Dasen et al. (1999) demonstrated that the appearance of 4 ventral pituitary cell types is mediated via the reciprocal interactions of these 2 transcription factors, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. This program includes a DNA binding-independent function of PIT1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to the generation of distinct cell phenotypes.
By homologous recombination, Johnson et al. (2012) generated mice lacking a composite E-box/GATA element in intron 4 of Gata2 corresponding to the conserved +9.5 kb composite element in intron 5 of human GATA2. Mice homozygous for deletion of the element died at approximately embryonic day 14 and exhibited severe hemorrhaging and variable edema. Mice heterozygous for the deletion were obtained at the expected numbers. Severe depletion of fetal liver hematopoietic stem/progenitor cells was observed in mice homozygous for the deletion. Johnson et al. (2012) concluded that GATA2 is important in conferring vascular integrity.
In 2 sisters and 4 unrelated patients with immunodeficiency-21 (IMD21; 614172), Hsu et al. (2011) identified a heterozygous C-to-T transition at nucleotide 1192 of the GATA2 gene, resulting in an arg398-to-trp (R398W) substitution. The R398W substitution occurred within the highly conserved zinc finger-2 domain of GATA2. The 2 sisters and 3 of the unrelated patients had been previously reported by Vinh et al. (2010). The patients had dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency.
Dickinson et al. (2011) identified the R398W mutation in a patient with IMD21 previously reported by Bigley et al. (2011).
In 3 unrelated patients with IMD21 (614172), Hsu et al. (2011) identified a heterozygous C-to-T transition at nucleotide 1061 of the GATA2 gene, resulting in a thr354-to-met (T354M) substitution. The T354M substitution occurred within the highly conserved zinc finger-2 domain of GATA2. One of these patients had previously been reported by Vinh et al. (2010).
Dickinson et al. (2011) identified the T354M mutation in a patient with IMD21 previously reported by Bigley et al. (2011).
In 3 multigenerational families with a predisposition to myelodysplastic syndrome (MDS; 614286) and acute myeloid leukemia (AML; 601626), Hahn et al. (2011) identified heterozygosity for the T354M mutation in exon 5 of the GATA2 gene that segregated with disease: all affected individuals who were tested in each family carried the mutation, as did some unaffected members. The mutation was not found in 695 nonleukemic ethnically matched controls. Luciferase reporter assay experiments demonstrated that T354M dramatically reduced induction of known GATA2-responsive enhancers compared to wildtype, with a dominant-negative effect. Microarray analysis revealed that T354M is an almost total loss-of-function mutant, and studies using HL60 promyelocytes showed differential effects on cellular differentiation and apoptosis compared to wildtype.
In a patient with IMD21 (614172), Hsu et al. (2011) identified a heterozygous C-to-T transition at nucleotide 751 of the GATA2 gene, resulting in a pro254-to-leu (P254L) substitution. The P254L substitution occurred before the zinc finger domains of GATA2 and was predicted to be damaging.
In a mother and daughter with IMD21 (614172), Hsu et al. (2011) identified a heterozygous 2,033-bp deletion within the GATA2 gene. The deletion removed exons 3 and 4 of GATA2, including the ATG start codon and Kozak sequence. These patients had previously been reported by Vinh et al. (2010).
In a patient with IMD21 (614172), Hsu et al. (2011) identified a heterozygous 12-bp deletion at nucleotide 1083 of the GATA2 gene. The deletion resulted in the in-frame removal of 4 amino acids beginning at arg361 within the loop of zinc finger-2. This patient had previously been reported by Vinh et al. (2010).
In a patient with IMD21 (614172), Hsu et al. (2011) identified a heterozygous 1-bp deletion (A) and 2-bp insertion (GC) at nucleotide 243 of the GATA2 gene, resulting in a frameshift and premature termination. This patient had previously been reported by Vinh et al. (2010).
In a patient with IMD21 (614172), previously reported by Bigley et al. (2011), Dickinson et al. (2011) identified a 1-bp insertion (G) at nucleotide 599 of the GATA2 cDNA. The insertion, which occurred in codon 200, was predicted to result in a frameshift, premature termination, and loss of the C-terminal zinc finger.
In a patient with IMD21 (614172), previously reported by Bigley et al. (2011), Dickinson et al. (2011) identified a G-to-T transversion in intron 4 of the GATA2 gene (1018-1G-T of the GATA2 cDNA). The mutation was predicted to cause skipping of exon 5 and deletion of amino acids 340 to 381, resulting in loss of the C-terminal zinc finger.
In 5 affected members over 2 generations of a family with primary lymphedema and myelodysplasia (614038), including 'patient 1' reported by Mansour et al. (2010), Ostergaard et al. (2011) identified heterozygosity for a 2-bp insertion (310insCC) in exon 2 of the GATA2 gene, predicted to cause a frameshift and premature termination. The mutation was not found in unaffected family members or in 300 unrelated control chromosomes.
In a brother and sister with primary lymphedema and myelodysplasia (614038) and their affected mother who had only minimal edema of the feet, Ostergaard et al. (2011) identified heterozygosity for a 1-bp insertion (230insC) in exon 2 of the GATA2 gene, predicted to cause a frameshift and premature termination. The brother was 'patient 5' reported by Mansour et al. (2010). The mutation was not found in 300 unrelated control chromosomes.
In a Chinese female patient with bilateral lower extremity and genital edema and acute myeloid leukemia (Emberger syndrome; 614038), Ostergaard et al. (2011) identified heterozygosity for a 1009C-T transition in exon 3 of the GATA3 gene, resulting in an arg337-to-ter (R337X) substitution. The mutation was not found in 300 unrelated control chromosomes.
In a sporadic male patient who developed genital and bilateral lower limb edema at 8 years of age and myelodysplasia at age 16 years (Emberger syndrome; 614038), who also had persistent warts on his fingers, Ostergaard et al. (2011) identified heterozygosity for a 1117T-C transition in exon 4 of the GATA2 gene, resulting in a cys373-to-arg (C373R) substitution at a conserved residue within the second C(4) zinc finger domain. The patient was 'patient 2' reported by Mansour et al. (2010). The mutation was not found in 300 unrelated control chromosomes. Functional analysis in transfected HEK293T cells demonstrated significant reduction in transactivation activity with C373R compared to wildtype. The patient died at 16 years of age.
In a sporadic male patient who developed genital and bilateral lower limb edema at 10 years of age and had a low CD4/CD8 ratio (Emberger syndrome; 614038), Ostergaard et al. (2011) identified heterozygosity for a 1082G-C transversion in exon 4 of the GATA2 gene, resulting in an arg361-to-leu (R361L) substitution at a conserved residue within the second C(4) zinc finger domain. The mutation was not found in 300 unrelated control chromosomes. Functional analysis in transfected HEK293T cells demonstrated significant reduction in transactivation activity with R361L compared to wildtype. Other features present in this patient included cutaneous warts with malignant transformation to anogenital dysplasia and sensorineural hearing loss.
In a father and son with myelodysplastic syndrome (MDS; 614286), Hahn et al. (2011) identified heterozygosity for a 3-bp deletion (1063delACA) in the GATA2 gene, resulting in deletion of a highly conserved threonine residue at position 355 (thr355del) in the zinc finger-2 (ZF2) domain. The mutation was not found in 695 nonleukemic ethnically matched controls. Luciferase reporter assay experiments demonstrated that the mutation dramatically reduced induction of known GATA2-responsive enhancers compared to wildtype, with a dominant-negative effect. Microarray analysis revealed that thr355del is an almost total loss-of-function mutant, and studies using HL60 promyelocytes showed differential effects on cellular differentiation and apoptosis compared to wildtype.
Johnson et al. (2012) identified a 27-year-old woman of European descent with IMD21 (614172). The woman lacked exonic mutations or mutations in upstream cis regulatory elements of GATA2. However, Johnson et al. (2012) found that she was heterozygous for a 28-bp deletion in a conserved composite E-box/GATA element in intron 5 at +9.5 kb (572+512del28). The patient was treated with long-term GMCSF (CSF2; 138960) and EPO (133170). One of the patient's 2 sons was heterozygous for the mutation. In addition, 4 unrelated families showed mendelian inheritance of the mutation, which was absent in over 400 control alleles from normal individuals.
In a girl with IMD21 (614172), originally reported by Biron et al. (1989), Mace et al. (2013) identified a heterozygous 4-bp insertion (c.1025GCCG) in the GATA2 gene, predicted to result in a frameshift and premature termination (Ala342GlyfsTer41). The patient had recurrent bacterial infections, disseminated varicella-zoster virus, cytomegalovirus infections, and severe herpes simplex infection. Laboratory studies showed leukopenia with severe NK-cell deficiency, and the patient subsequently developed aplastic anemia. She died during hematopoietic stem cell transplantation.
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