Alternative titles; symbols
HGNC Approved Gene Symbol: GATA1
SNOMEDCT: 718196002;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:48,786,590-48,794,311 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Anemia, X-linked, with/without neutropenia and/or platelet abnormalities | 300835 | X-linked recessive | 3 |
| Hemolytic anemia due to elevated adenosine deaminase | 301083 | X-linked recessive | 3 | |
| Leukemia, megakaryoblastic, with or without Down syndrome, somatic | 159595 | 3 | ||
| Thrombocytopenia with beta-thalassemia, X-linked | 314050 | X-linked recessive | 3 | |
| Thrombocytopenia, X-linked, with or without dyserythropoietic anemia | 300367 | X-linked recessive | 3 |
The GATA1 gene encodes a zinc finger DNA-binding transcription factor that plays a critical role in the normal development of hematopoietic cell lineages. The protein contains an N-terminal region that confers transcriptional activity and a C-terminal domain that mediates binding to DNA and other factors (summary by Calligaris et al., 1995).
Vertebrate erythroid cells contain a tissue-specific transcription factor referred to as ERYF1 (Evans et al., 1988), GF1 (Martin et al., 1989), NFE1 (Wall et al., 1988), or GATA1 (Gumucio et al., 1991). At least 4 other proteins--Sp1 (189906), Oct1 (164175), a CACCC-binding protein, and a protein with an affinity for the -200 region--bind to the gamma-globin promoter between nucleotides -260 and -137 (Gumucio et al., 1991). Binding sites for these transcription factors are widely distributed in the promoters and enhancers of the globin gene family and of other erythroid-specific genes. Aberrant binding of the human factor to a mutant site has been implicated in one type of hereditary persistence of fetal hemoglobin (Martin et al., 1989). Trainor et al. (1990) cloned the cDNA for the human ERYF1 gene. The central third of the cDNA, containing 2 'finger' motifs, is almost identical to that of chicken and mouse. The N- and C-terminal thirds of the human protein are similar to those of mouse but are strikingly different from the corresponding domains in the chicken. By means of a systematic functional analysis of the human gamma-globin promoter to identify its activator domains, Lin et al. (1992) identified the CACCC region and the region containing the binding sites for protein GATA1 as activator domains. GATA1 was the founding member of a family of DNA-binding proteins that recognize the motif WGATAR (in which W is A or T, and R is A or G) through a conserved multifunctional domain consisting of 2 C4-type zinc fingers.
Calligaris et al. (1995) identified 2 different GATA1 isoforms resulting from alternative translation initiation sites in murine and human erythroid cells. The GATA1 gene encodes a 1.8-kb mRNA yielding a full-length 47-kD protein and a shorter 40-kD protein, termed GATA1s. GATA1s uses a translation initiation site at codon 84, and thus lacks the N-terminal transactivation domain. Both isoforms showed virtually identical DNA-binding activity and could form homo- or heterodimers, but the shorter GATA1s isoform was less active than the full-length protein in transactivating a GATA-dependent reporter gene.
GATA1 and friend of GATA1 (FOG; ZFPM1; 601950) are each essential for erythroid and megakaryocyte development. FOG, a zinc finger protein, interacts with the amino (N) finger of GATA1 and cooperates with GATA1 to promote differentiation. To determine whether this interaction is critical for GATA1 action, Crispino et al. (1999) selected GATA1 mutants in yeast that failed to interact with FOG but retained normal DNA binding, as well as a compensatory FOG mutant that restored interaction. These GATA1 mutants did not promote erythroid differentiation of GATA1-deficient erythroid cells. Differentiation was rescued by the second-site FOG mutant. Thus, Crispino et al. (1999) concluded that interaction of FOG with GATA1 is essential for the function of GATA1 in erythroid differentiation.
De Maria et al. (1999) demonstrated that immature erythroid cells express several death receptors whose ligands are produced by mature erythroblasts. Exposure of erythroid progenitors to mature erythroblasts or death-receptor ligands resulted in caspase-mediated degradation of the transcription factor GATA1, which is associated with impaired erythroblast development. Expression of a caspase-resistant GATA1 mutant, but not of the wildtype gene, completely restored erythroid expansion and differentiation following the triggering of death receptors, indicating that there is regulatory feedback between mature and immature erythroblasts through caspase-mediated cleavage of GATA1. Similarly, erythropoiesis blockade following erythropoietin (133170) deprivation was largely prevented by the expression of caspase-inhibitory proteins or caspase-resistant GATA1 in erythroid progenitors. De Maria et al. (1999) concluded that caspase-mediated cleavage of GATA1 may therefore represent an important negative control mechanism in erythropoiesis.
Blobel et al. (1998) found that, in mouse nonhematopoietic cells, Cbp (600140) stimulated Gata1 transcriptional activity. Cbp and Gata1 also coimmunoprecipitated from nuclear extracts of mouse erythroid cells. Interaction mapping pinpointed the contact sites to the zinc finger region of Gata1 and to the E1A-binding region of Cbp. Expression of adenovirus E1A revealed that the interaction of Cbp with Gata1 in erythroid cells affected differentiation and expression of endogenous Gata1 target genes.
Horak et al. (2002) demonstrated the usefulness of chromatin immunoprecipitation (chIp) analysis for mapping GATA1 binding sites in the beta-globin locus, and suggested a general utility of the method for mapping transcription factor binding sites within the beta-globin locus and throughout the genome. This approach involves chIp of protein-DNA complexes and microarray hybridization of labeled, immunopurified DNA (chip).
Stumpf et al. (2006) found that mouse progenitor cells deficient in the Mediator complex component Med1 (PPARBP; 604311) had a defect in production of erythroid burst-forming units and colony-forming units, but not in forming myeloid colonies. Med1 interacted physically with Gata1, and in transcription assays, Med1 deficiency led to a defect in Gata1-mediated transactivation. Chromatin immunoprecipitation assays showed Mediator complex components at Gata1-occupied enhancer sites. Stumpf et al. (2006) concluded that MED1 acts as a pivotal coactivator for GATA1 in erythroid development.
Ribeil et al. (2007) demonstrated that during erythroid differentiation but not apoptosis, the chaperone protein Hsp70 (140550) protects GATA1 from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 colocalizes and interacts with GATA1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA1. In an in vitro assay, Hsp70 protected GATA1 from caspase-3 (CASP3; 600636)-mediated proteolysis through its peptide-binding domain. Ribeil et al. (2007) used RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin. This led to GATA1 cleavage, a decrease in hemoglobin content, downregulation of the expression of the antiapoptotic protein Bcl-XL (see 600039), and cell death by apoptosis. These effects were abrogated by the transduction of a caspase-resistant GATA1 mutant. Thus, Ribeil et al. (2007) concluded that in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active CASP3 from cleaving GATA1 and inducing apoptosis.
HSP27 (HSPB1; 602195) is a ubiquitin-binding protein involved in proteasomal degradation of certain proteins under stress conditions. De Thonel et al. (2010) found that HSP27 was involved in proteasome-mediated degradation of GATA1. Knockdown of HSP27 or overexpression of GATA1 inhibited differentiation of primary cultured human erythroid cells and the K562 erythroleukemia cell line. HSP27-mediated GATA1 degradation was reduced by proteasome inhibitors and required prior acetylation of GATA1 and serine phosphorylation of HSP27 via the p38 MAP kinase (MAPK14; 600289) pathway.
Yu et al. (2010) observed erythropoietic defects in fetal liver of Senp1 (612157) -/- mice. These defects were accompanied by reduced activity of Gata1 and reduced expression of Gata1 target genes due to accumulation of sumoylated Gata1. Mechanistic studies in human cells showed that SENP1 directly desumoylated GATA1 and thereby regulated GATA1 DNA-binding activity, GATA1-dependent EPOR (133171) expression, and erythropoiesis. They concluded that SENP1 promotes GATA1 activation and subsequent erythropoiesis by desumoylating GATA1.
Liu et al. (2014) identified a GATA1-binding site in intron 1 of the PSTPIP2 gene (616046) and found that binding of GATA1 to this site downregulated PSTPIP2 expression during phorbol ester- or thrombopoietin (THPO; 600044)-induced differentiation in human and mouse megakaryocytic cell lines. GATA1-dependent downregulation of PSTPIP2 permitted activation of the signaling cascade for megakaryocyte growth and differentiation.
Fulco et al. (2016) presented a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. Fulco et al. (2016) assessed more than 1 megabase of sequence in the vicinity of 2 essential transcription factors, MYC (190080) and GATA1 and identified 9 distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the 7 enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. Fulco et al. (2016) suggested that this CRISPRi-based approach could be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.
Hoppe et al. (2016) used novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 and PU.1 (SPI1; 165170) and analyzed individual hematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics were incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, the findings suggested that these transcription factors are only executing and reinforcing lineage choice once made. Hoppe et al. (2016) concluded that their results challenged the prevailing model of early myeloid lineage choice, which assumed that lineage choice is initiated and determined by stochastic fluctuations of cross-antagonistic transcription factor pairs.
Zon et al. (1990) used cross-hybridization to the finger domain of murine GF-1 to isolate cDNA encoding the human homolog. By hybridization to panels of human-rodent DNAs, they assigned the human locus to chromosome Xp21-p11. By a combination of in situ hybridization and analysis of human-rodent hybrid cell lines, Caiulo et al. (1991) demonstrated that the NFE1 gene is located in Xp11.23.
Chapman et al. (1991) identified a single X-chromosome locus in the mouse, Gf-1, and by analysis of recombinants from 203 backcross progeny, mapped the locus to the proximal part of the chromosome, coincident with the Cybb locus and proximal to the Otc locus.
Germline GATA1 Mutations Causing Hematopoietic Disorders
In 2 half brothers, born of the same mother, with X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA; 300367), Nichols et al. (2000) identified a germline hemizygous mutation in the GATA1 gene (V205M; 305371.0001). In vitro functional expression studies showed that the V205M mutation abrogated the interaction between GATA1 and FOG1 (ZFPM1; 601950), inhibiting the ability of GATA1 to rescue erythroid differentiation in an erythroid cell line deficient for GATA1. The findings underscored the importance of the FOG1-GATA1 associations in both megakaryocyte and erythroid development, and suggested that other X-linked anemias or thrombocytopenias may be caused by defects in the GATA1 gene. The GATA1 gene was chosen for study because targeted mutagenesis in embryonic stem cells and mice revealed roles for the Gata1 gene in erythrocyte and megakaryocyte differentiation (see ANIMAL MODEL and Fujiwara et al., 1996; Shivdasani et al., 1997).
In a family with isolated X-linked thrombocytopenia without anemia but with some dyserythropoietic features, Freson et al. (2001) identified an asp218-to-gly mutation (305371.0002) in the GATA1 gene, which resulted in a weaker interaction with FOG1.
Yu et al. (2002) identified an arg216-to-gln substitution in the GATA1 N finger (305371.0006) as the cause of X-linked thrombocytopenia with beta-thalassemia (314050). By analyzing mutant and wildtype GATA1 proteins expressed in transfected COS cells, they found that the mutation did not affect interaction between GATA1 and a single GATA-binding sequence. It did, however, reduce the affinity between GATA1 and palindromic GATA sites. GATA1 carrying this mutation also interacted normally with FOG1 and could direct differentiation in a murine erythroblast cell line, although somewhat less efficiently than the wildtype protein.
In 8 affected males in 2 generations of a family with X-linked anemia with or without neutropenia and/or platelet abnormalities (XLANP; 300835), Hollanda et al. (2006) identified a germline splice site mutation in the GATA1 gene (332G-C, V74L; 305371.0008) resulting in the synthesis of only the short variant, GATA1s. The data suggested that GATA1s alone, produced in low or normal levels, is not sufficient to support normal erythropoiesis. Acquired somatic mutations in the GATA1 gene that result in synthesis of GATA1s have been found in individuals with Down syndrome with both transient myeloproliferative disorder and acute megakaryoblastic leukemia (see 190685). However, none of the patients reported by Hollanda et al. (2006) developed leukemia.
Ludwig et al. (2014) found that the transcriptional signature of GATA1 target genes was globally and specifically decreased in cells from patients with Diamond-Blackfan anemia-1 (DBA1; 105650) due to mutation in the RPS19 gene (603474). The mRNA level of GATA1 was not decreased, but protein and activity levels of GATA1 were decreased, likely reflecting decreased protein translation due to ribosomal abnormalities caused by mutation in RPS19. Similar results were observed with mutations in other DBA-associated ribosomal genes, again reflecting impaired translation. Ludwig et al. (2014) characterized the 5-prime end of GATA1 mRNA and found that it was highly structured, which influences translation efficiency. Further in vitro studies demonstrated that the defective erythropoiesis in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 levels. The findings provided a mechanistic link between mutations in GATA1 and phenotypes resembling DBA, which is usually associated with mutations in ribosomal subunit genes, and also suggested that dysregulated GABA1 protein translation may be a key factor in mediating the erythroid-specific defect observed in DBA.
In 3 unrelated male patients with hemolytic anemia due to elevated erythrocyte adenosine deaminase (HAEADA; 301083), Ludwig et al. (2022) identified hemizygous missense mutations affecting the same residue in the GATA1 gene (R307C, 305371.0012 and R307H, 305371.0013). The mutations affected a conserved residue in an intrinsically disordered region (IDR) in the C-terminal domain. The mutations, which were found by whole-exome sequencing, were not present in the gnomAD database. Patient-derived erythroid cells showed impaired differentiation, reduced proliferation, and altered morphology compared to controls, which could be partially rescued by expression of wildtype GATA1. Cells transduced with the mutations showed increased erythrocyte ADA (608958) levels and increased ADA mRNA levels compared to controls. RNA-seq analysis suggested differential expression of genes involved in hematopoiesis and terminal erythroid maturation. Mouse-derived Gata1-null cells transduced with Gata1 showed induction of Ter119, a marker for erythroid differentiation; cells transduced with the R307C/H mutants had reduced Ter119 expression. The R307C/H mutations partially disrupted a predicted nuclear localization signal, and the mutant proteins showed a 40% reduction in the nucleus and increased retention in the cytoplasm compared to wildtype. Additional RNA-seq analysis results were consistent with altered transcriptional activity of the mutants toward canonical GATA1 target genes. Further studies of mutant cells showed impaired chromatin accessibility and DNA binding associated with the mutations, consistent with the observed changes in gene expression that pointed to disrupted transcription regulation. Overall, the findings indicated a primary erythroid defect of terminal differentiation resulting from specific mutations in the GATA1 master transcription factor.
Somatic GATA1 Mutations
Children with Down syndrome (190685) have a 10- to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL; see 159595). Some pediatric cases of AMKL are associated with the 1;22 translocation that results in a mutant fusion protein involving RBM15 (606077) on chromosome 1 and MKL1 (606079) on chromosome 22. Wechsler et al. (2002) showed that leukemic cells from individuals with Down syndrome-related AMKL had somatic mutations in the GATA1 gene (see, e.g., 305371.0004). Each mutation resulted in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevented synthesis of full-length GATA1 and resulted in synthesis of the shorter alternatively translated variant (GATA1s) that is initiated downstream. Wechsler et al. (2002) showed that GATA1s, which lacks the N-terminal transactivation domain but retains both zinc finger domains and the whole C terminus, interacts with the FOG1 cofactor to the same extent as does full-length GATA1, but has a reduced transactivation potential. The findings suggested that loss of wildtype GATA1 constitutes 1 step in the pathogenesis of AMKL in Down syndrome.
Look (2002) reviewed the mechanism by which GATA1 mutations might interact with trisomy 21 to result in acute megakaryoblastic leukemia. He pointed out that several lines of evidence indicated that at least 2 classes of mutations are needed to transform a normal hematopoietic stem cell (HSC) into a clonal acute myeloid leukemia. One class imparts a myeloproliferative or survival advantage, as illustrated by activating mutations in FLT3 (136351), encoding a receptor tyrosine kinase, or the increased dosage of genes in chromosome 21 in persons with Down syndrome. To generate overt leukemia, a second class of genetic alterations must produce lineage-specific blocks in differentiation. The mutations responsible for this step have been demonstrated mainly in genes encoding chimeric transcription factors produced by chromosomal translocation. Pabst et al. (2001) identified mutations in the CEBPA gene (116897) that are associated with acute myeloid leukemia, and, like GATA1, produce lineage-specific blocks in differentiation. Both CEBP1 and GATA1 are transcription factors that play pivotal roles in myeloid lineage commitment.
As many as 10% of infants with Down syndrome present with transient myeloproliferative disorder (TMD) at or shortly after birth. TMD is characterized by an abundance of blasts within peripheral blood and liver, and undergoes spontaneous remission in a majority of cases. TMD may be a precursor to AMKL, with an estimated 30% of TMD patients developing AMKL within 3 years. Mutations in GATA1 are associated with the AMKL of Down syndrome. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, Mundschau et al. (2003) analyzed GATA1 in somatic DNA from blasts derived from TMD patients. They found that GATA1 was mutated in the TMD blasts from every infant examined. These results demonstrated that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in myeloid leukemogenesis in Down syndrome. Hitzler et al. (2003) likewise presented evidence that GATA1 mutations are an early event, and that AMKL arises from latent transient leukemia clones following initial apparent remission. All 7 patients reported by Mundschau et al. (2003) and almost all of the patients studied by Hitzler et al. (2003) had deletions or insertions in the GATA1 gene rather than nucleotide substitutions.
Somatic mutations in exon 2 of the transcription factor GATA1 have been detected in essentially all cases of megakaryoblastic leukemia and transient myeloproliferative disorder (Gurbuxani et al., 2004). Taub et al. (2004) presented evidence of prenatal origin of GATA1 mutations by study of fetal liver from cases of Down syndrome.
Ahmed et al. (2004) studied genomic DNA from 12 AMKL and 4 TMD cases (including neonatal, prediagnosis samples in 4 of the 16), neonatal blood spots from 21 Down syndrome children without clinically evident TMD or AMKL, and 62 non-Down syndrome cord blood samples. GATA1 mutations were present in all TMD and AMKL cases and at birth in 3 of 4 children without known clinical TMD who later developed AMKL. GATA1 mutations were present at birth in 2 of 21 Down syndrome neonates who had not yet developed AMKL at the ages of 26 and 31 months. GATA1 mutations were not detected in 62 non-Down syndrome cord blood samples. In 4 AMKL patients, multiple independent GATA1 mutations were observed. Ahmed et al. (2004) concluded that GATA1 mutations occur in utero in most Down syndrome TMD and AMKL, that they may occur without clinical signs of disease, and that multiple separate GATA1 mutant clones can occur in an individual.
To define the mechanisms governing the transcriptional regulation of Gata1, McDevitt et al. (1997) replaced upstream sequences that included a DNase I hypersensitive region with a neomycin-resistance cassette by homologous recombination in mouse embryonic stem cells and generated mice either harboring this mutation or lacking the selection cassette altogether. Mice lacking the DNase I hypersensitive region and expressing the neomycin-resistance cassette had marked impairment in the rate or efficiency of erythroid cell maturation due to a modest 4- to 5-fold decrease in Gata1 expression. The phenotype of embryos was, however, far less severe than that seen in Gata1 -/- embryos, which invariably died by embryonic day 11 due to proerythroblast arrest and apoptosis of primitive erythroid precursors. McDevitt et al. (1997) argued that by producing a 'knockdown' mutation, they revealed a concentration-dependent role of GATA1 in terminal erythroid cell maturation.
Whyatt et al. (2000) demonstrated that overexpression of GATA1 in erythroid cells inhibits their differentiation, leading to a lethal anemia. Using chromosome-X inactivation of a Gata1 transgene and chimeric animals, Whyatt et al. (2000) showed that this defect is intrinsic to erythroid cells, but nevertheless cell-nonautonomous. Usually, cell nonautonomy is thought to reflect aberrant gene function in cells other than those that exhibit the phenotype. On the basis of their data, Whyatt et al. (2000) proposed an alternative mechanism in which a signal originating from wildtype erythroid cells restores normal differentiation to cells overexpressing GATA1 in vivo. The existence of such a signaling mechanism indicates that previous interpretations of cell-nonautonomous defects may be erroneous in some cases and may in fact assign gene function to incorrect cell types.
Lyons et al. (2002) demonstrated that a nonsense mutation in the Gata1 gene was responsible for the disorder in the 'bloodless' zebrafish. It is characterized by a severe reduction in blood cell progenitors and few or no blood cells at the onset of circulation. Study of the mutation shed new light on Gata1 structure and function in vivo, demonstrated that Gata1 plays an essential role in zebrafish hematopoiesis with significant conservation of function between mammals and zebrafish, and offered a tool for future studies of the hematopoietic pathway.
To assess functions of the association between Gata1 and Fog1 (601950) during mouse development, Shimizu et al. (2004) generated a mutant Gata1 gene that contained a substitution of glycine-205 for valine (V205G), which abrogated its association with Fog1. They examined whether the transgenic expression of mutant Gata1 rescued Gata1 germline mutants from embryonic lethality. In high expressor lines they observed that the mutant GATA1 rescued Gata1-deficient mice from embryonic lethality at the expected frequency, showing that excess mutant Gata1 can eliminate the lethal anemia that is due to GATA1 deficiency. In contrast, transgene expression comparable to the endogenous Gata1 level resulted in a much lower frequency of rescue, indicating that the GATA1/FOG1 association is critical for normal embryonic hematopoiesis. Rescued mice in these analyses exhibited thrombocytopenia and displayed dysregulated proliferation and impaired cytoplasmic maturation of megakaryocytes. Although anemia was not observed under steady-state conditions, stress erythropoiesis was attenuated in the rescued mice. The findings revealed an indispensable role for the association of GATA1 and FOG1 during late-state megakaryopoiesis and provided a unique model for X-linked thrombocytopenia with inherited GATA1 mutations.
Acquired mutations in GATA1 are found in megakaryoblasts from nearly all individuals with Down syndrome with transient myeloproliferative disorder (TMD) and the related acute megakaryoblastic leukemia (AMKL). The mutations lead to production of a variant GATA1 protein (GATA1s) that is truncated at its N terminus. To understand the biologic properties of GATA1s and its relation to TMD and AMKL, Li et al. (2005) used gene targeting to generate Gata1 alleles that express Gata1s in mice. They showed that the dominant action of Gata1s leads to hyperproliferation of a unique, previously unrecognized yolk sac and fetal liver progenitor, which they proposed accounts for the transient nature of TMD and the restriction of AMKL to infants. These observations raised the possibility that target cells in other leukemias of infancy and early childhood are distinct from those in adult leukemias, and underscored the interplay between specific oncoproteins and potential target cells.
In 2 half brothers, born of the same mother, with X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA; 300367), Nichols et al. (2000) identified a germline hemizygous 613G-A transition in the GATA1 gene, resulting in a val205-to-met (V205M) substitution in a highly conserved residue in the N-terminal zinc finger that is essential for direct association of GATA1 with its essential cofactor FOG1 (ZFPM1; 601950). The mutation was not found in 50 control females. In vitro functional expression studies using mouse cDNA in COS cells showed a reduced interaction between mutant Gata1 and Fog1. The mutant protein was also impaired in its ability to promote erythroid differentiation in vitro. Both pregnancies were complicated by severe fetal anemia requiring in utero red blood cell transfusions. The boys were anemic and severely thrombocytopenic from birth, and both eventually required a bone marrow transplant. Examination prior to the transplant showed abnormalities in the erythrocyte and platelet lineages. Peripheral blood showed a paucity of platelets, and erythrocytes were abnormal in size and shape (poikilocytosis and anisocytosis). Both boys also had cryptorchidism. There were 3 asymptomatic female sibs. Their mother, who was heterozygous for the mutation, had mild chronic thrombocytopenia.
Freson et al. (2001) described a family with isolated X-linked macrothrombocytopenia without anemia but with some dyserythropoietic features (300367) in 13 males in 9 sibships of 3 generations connected through carrier females. A novel mutation in the GATA1 gene, asp218 to gly (D218G), resulted in a weaker interaction with FOG1 (601950). Electron microscopy of the patients' platelets showed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes.
Mehaffey et al. (2001) described a family in which 4 males in 2 generations related through female carriers had thrombocytopenia characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis with no measurable anemia (300367). By sequencing the entire coding region of GATA1, they identified a GG-to-TC change at nucleotides 622-623 that resulted in a gly208-to-ser (G208S) substitution within a highly conserved portion of the N-terminal zinc finger domain. Although not required for DNA binding, the gly208 allele of GATA1 is involved in direct interaction with FOG1 (601950), a cofactor required for normal megakaryocytic and erythroid development.
In leukemic cells from children with Down syndrome and acute megakaryoblastic leukemia (190685), Wechsler et al. (2002) found a somatic 4-bp insertion in exon 2 of the GATA1 gene.
Freson et al. (2002) described a 2-generation family with X-linked thrombocytopenia and anemia (300367) in which affected individuals had a 652G-T transversion in the GATA1 gene, resulting in an asp218-to-tyr (D218Y) substitution. Zinc finger interaction studies revealed a stronger loss of affinity of D218Y-GATA1 than of D218G-GATA1 (305371.0002) for the essential transcription factor FOG1 (601950) and a disturbed GATA1 self-association. Comparison of the phenotypic characteristics of patients from both families revealed that platelet and erythrocyte morphology as well as expression levels of the platelet GATA1-target gene products were more profoundly disturbed for the hemizygote D218Y mutation. The D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of a female carrier, while her leukocytes showed a skewed X-inactivation pattern. The authors concluded that the nature of the amino acid substitution at position 218 of the N-terminal zinc finger of GATA1 may be of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients and possibly also in inducing skewed X inactivation.
Yu et al. (2002) identified an arg216-to-gln (R216Q) mutation in the N finger of GATA1 in a family with X-linked thrombocytopenia with beta-thalassemia (XLTT; 314050). The family had previously been reported by Thompson et al. (1977).
Tubman et al. (2007) identified an R216Q substitution in affected members of a family with a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of the so-called 'gray platelet syndrome' (139090). In a letter, Balduini et al. (2007) stated that the family reported by Tubman et al. (2007) had a phenotype consistent with X-linked thrombocytopenia with beta-thalassemia (XLTT) and that the classification as 'X-linked gray platelet syndrome' is a misnomer risking confusion in the literature. They noted that deficiency of platelet alpha-granules can be a feature of XLTT. In response, the original authors (Neufeld et al., 2007) agreed that the disorder in the family may be classified as an example of a unique disorder, i.e., XLTT, but endorsed its classification as 'a unique kind of GPS, inherited in X-linked fashion, with platelets indistinguishable by experts from autosomal GPS (at the light microscope and ultrastructure level).'
In leukemic cells derived from a 48-year-old woman with acute megakaryoblastic leukemia, Harigae et al. (2004) identified a 20-bp duplication in exon 2 of the GATA1 gene, resulting in the introduction of a premature stop codon in the gene sequence encoding the N-terminal activation domain. This was the first report of a GATA1 mutation in AMKL cells from a patient who did not have Down syndrome (190685) or acquired trisomy 21.
Hollanda et al. (2006) described a Brazilian family in which 8 males in 2 generations had X-linked anemia with or without neutropenia and/or platelet abnormalities (XLANP; 300835). Affected members had a 332G-C transversion at the boundary of exon 2 of the GATA1 gene, predicted to result in a val74-to-leu (V74L) substitution (Sankaran et al., 2012). The mutation led to splice site changes that prevented the translation of the full-length GATA1 protein and allowed the generation of only GATA1s in the affected males. Unaffected carrier females were heterozygous for this mutation. In the majority of affected individuals, Hollanda et al. (2006) observed abnormal morphology of erythrocytes and granulocytes in peripheral blood films as well as bone marrow with trilineage dysplasia and hypocellularity of erythroid and granulocytic lineages, and with normal or increased numbers of micromegakaryocytes. Neutropenia of a variable degree was present in the affected individuals. Data from the family strongly suggested that GATA1s is not sufficient to support normal hematopoiesis in adults, in contrast to the animal model findings of Li et al. (2005).
In 2 brothers with congenital anemia, occasional reductions in neutrophil count, increased fetal hemoglobin, and low platelet count in 1 patient, Sankaran et al. (2012) identified a 332G-C transversion in the last nucleotide of the exon 2 donor splice site of the GATA1 gene. The transversion, which was identified by whole-exome sequencing, was also predicted to result in a V74L substitution. RT-PCR studies of patient samples showed that most of the GATA1 mRNA was for GATA1s, although there were trace amounts of the full-length protein. Their unaffected mother, who also carried the mutation, had about 53% levels of the full-length protein. Both patients showed a favorable response to corticosteroid therapy. Neither showed increased bleeding or an increased propensity for infection. Bone marrow biopsy showed erythroid hypoplasia without abnormalities of the other hematopoietic lineages, and the boys were given a diagnosis of Diamond-Blackfan anemia (DBA; 105650); however, erythrocyte adenosine deaminase in the boys was not elevated, as is usually observed in Diamond-Blackfan anemia.
In 3 Swedish brothers, 1 of whom was a maternal half brother, with features consistent with DBA, Klar et al. (2014) identified a hemizygous c.220G-C transversion in the GATA1 gene, which the authors stated was the same mutation as that identified by Sankaran et al. (2012) in patients with a phenotype reminiscent of DBA. Haplotype analysis indicated that the mutations occurred independently in the 2 families. Klar et al. (2014) noted that loss of the long GATA1 isoform seems to result in hematologic abnormalities.
In a 3.5-year-old boy with X-linked anemia that responded to corticosteroid treatment (300835), Sankaran et al. (2012) identified a 1-bp deletion (332delG) in exon 2 of the GATA1 gene at the same nucleotide involved in 305371.0008. The 1-bp deletion was predicted to favor production of GATA1s as a result of impaired splicing and frameshift of the full-length open reading frame. The patient, who presented at age 6 weeks, did not have other hematologic abnormalities, but fetal hemoglobin was increased. Erythrocyte adenosine deaminase was not elevated. This boy was 1 of 62 male probands with a clinical diagnosis of Diamond-Blackfan anemia (DBA; 105650) without known mutations who was studied for GATA1 mutations.
In a 3-year-old boy with X-linked thrombocytopenia with beta-thalassemia (314050) and anemia, Phillips et al. (2007) identified a hemizygous mutation in the GATA1 gene, resulting in an arg216-to-trp (R216W) substitution in a highly conserved residue in the N-terminal zinc finger. The patient presented with a photosensitive bullous dermatosis and was found to have hirsutism, splenomegaly, and increased uroporphyrin with decreased UROS (606938) activity (21% of normal), consistent with a clinical diagnosis of congenital erythropoietic porphyria (CEP; 263700). However, sequencing of the UROS gene was negative. Laboratory studies showed microcytic anemia with increased reticulocytes, thrombocytopenia, increased fetal hemoglobin (59.5%), and beta-thalassemia. Bone marrow biopsy was hypercellular with dyserythropoiesis, nuclear bridging, and occasional multinucleated red cells. Megakaryocytes were decreased in number. He underwent a stem cell transplant, which was successful. The patient's mother and maternal grandmother carried the mutation in heterozygous state. The mother had had multiple first-trimester spontaneous abortions, but no signs of porphyria. The grandmother had chronic anemia and thrombocytopenia. The GATA1 gene regulates expression of UROS in developing erythrocytes, which explained the decreased UROS activity and features of porphyria. The R216W mutation affects the same residue as that reported by Yu et al. (2002) (R216Q; 305371.0006) in a family with X-linked thrombocytopenia with beta-thalassemia, but a slightly different phenotype: the anemia was less severe and fetal hemoglobin levels were not as elevated. Phillips et al. (2007) postulated that the larger, more hydrophobic tryptophan in their family would affect GATA1 binding to the UROS promoter more significantly than the smaller glutamine described by Yu et al. (2002). The striking fetal hemoglobin in the patient reported by Phillips et al. (2007) also suggested a role for GATA1 in globin chain switching.
In an Italian boy with X-linked anemia (300835), Parrella et al. (2014) identified a hemizygous c.2T-C transition in the initiation codon of the GATA1 gene. The mutation, which was found by direct sequencing of the GATA1 gene among 23 Italian patients with a clinical diagnosis of Diamond-Blackfan anemia, was inherited from the unaffected mother. The mutation was predicted to result in loss of the long GATA1 isoform.
In in vitro cellular studies, Ludwig et al. (2014) demonstrated that the c.2T-C mutant predominantly produced the short isoform of GATA1 lacking the first 83 amino acids, but a low level of full-length GATA1 was also produced.
In a 3-year-old boy (patient 1) of Irish/English descent with hemolytic anemia due to elevated adenosine deaminase (HAEADA; 301083), Ludwig et al. (2022) identified a hemizygous C-T transition (chrX.48,652,248C-T, GRCh37) in the GATA1 gene, resulting in an arg307-to-cys (R307C) substitution at a conserved residue in an intrinsically disordered region (IDR) in the C-terminal domain. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Patient erythroid cells showed a mildly elevated ADA level at 14.4 IU/gHb. Patient-derived erythroid cells showed impaired differentiation, reduced proliferation, and altered morphology compared to controls, which could be partially rescued by expression of wildtype GATA1. Cells transduced with the mutations showed increased erythrocyte ADA levels and increased ADA mRNA levels compared to controls. The R307C mutation partially disrupted a predicted nuclear localization signal, and the mutant protein showed a 40% reduction in the nucleus and increased retention in the cytoplasm compared to wildtype. RNA-seq analysis results were consistent with altered transcriptional activity of the mutants toward canonical GATA1 target genes. Mutant cells showed impaired chromatin accessibility and DNA binding associated with the mutations, consistent with the observed changes in gene expression that pointed to disrupted transcription regulation.
In 2 unrelated Japanese men (P2 and P3) with hemolytic anemia due to elevated adenosine deaminase (HAEADA; 301083), Ludwig et al. (2022) identified a hemizygous G-A transition (chrX.48,652,249G-A, GRCh37) in the GATA1 gene, resulting in an arg307-to-his (R307H) substitution at a conserved residue in an intrinsically disordered region (IDR) in the C-terminal domain. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. P2 had previously been reported by Kanno et al. (1988) and P3 had previously been reported by Ogura et al. (2016). ADA levels in the patients were elevated: P2 had an ADA of 88.6 IU/gHb, and his mother, who presumably carried the mutation, had a ADA of 1.74 IU/gHb; P3 had an ADA of 39.7 IU/gHb, and his mother, who presumably carried the mutation, had an ADA of 7.40 IU/gHb. Patient-derived erythroid cells showed impaired differentiation, reduced proliferation, and altered morphology compared to controls, which could be partially rescued by expression of wildtype GATA1. Cells transduced with the mutations showed increased erythrocyte ADA levels and increased ADA mRNA levels compared to controls. The R307C mutation partially disrupted a predicted nuclear localization signal, and the mutant protein showed a 40% reduction in the nucleus and increased retention in the cytoplasm compared to wildtype. RNA-seq analysis results were consistent with altered transcriptional activity of the mutants toward canonical GATA1 target genes. Mutant cells showed impaired chromatin accessibility and DNA binding associated with the mutations, consistent with the observed changes in gene expression that pointed to disrupted transcription regulation.
Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., O'Marcaigh, A., Wynn, R., Stevens, R., Addison, M., King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. Natural history of GATA1 mutations in Down syndrome. Blood 103: 2480-2489, 2004. [PubMed: 14656875] [Full Text: https://doi.org/10.1182/blood-2003-10-3383]
Balduini, C. L., De Candia, E., Savoia, A. Why the disorder induced by GATA1 arg216gln mutation should be called 'X-linked thrombocytopenia with thalassemia' rather than 'X-linked gray platelet syndrome'. (Letter) Blood 110: 2770-2771, 2007. [PubMed: 17881640] [Full Text: https://doi.org/10.1182/blood-2007-03-080978]
Blobel, G. A., Nakajima, T., Eckner, R., Montminy, M., Orkin, S. H. CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. Proc. Nat. Acad. Sci. 95: 2061-2066, 1998. [PubMed: 9482838] [Full Text: https://doi.org/10.1073/pnas.95.5.2061]
Caiulo, A., Nicolis, S., Bianchi, P., Zuffardi, O., Bardoni, B., Maraschio, P., Ottolenghi, S., Camerino, G., Giglioni, B. Mapping the gene encoding the human erythroid transcriptional factor NFE1-GF1 to Xp11.23. Hum. Genet. 86: 388-390, 1991. [PubMed: 1999341] [Full Text: https://doi.org/10.1007/BF00201840]
Calligaris, R., Bottardi, S., Cogoi, S., Apezteguia, I., Santoro, C. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc. Nat. Acad. Sci. 92: 11598-11602, 1995. [PubMed: 8524811] [Full Text: https://doi.org/10.1073/pnas.92.25.11598]
Chapman, V. M., Stephenson, D. A., Mullins, L. J., Keitz, B. T., Disteche, C., Orkin, S. H. Linkage of the erythroid transcription factor gene (Gf-1) to the proximal region of the X chromosome of mice. Genomics 9: 309-313, 1991. [PubMed: 2004781] [Full Text: https://doi.org/10.1016/0888-7543(91)90258-g]
Crispino, J. D., Lodish, M. B., MacKay, J. P., Orkin, S. H. Use of altered specificity mutants to probe a specific protein-protein interaction in differentiation: the GATA-1:FOG complex. Molec. Cell 3: 219-228, 1999. [PubMed: 10078204] [Full Text: https://doi.org/10.1016/s1097-2765(00)80312-3]
De Maria, R., Zeuner, A., Eramo, A., Domenichelli, C., Bonci, D., Grignani, F., Srinivasula, S. M., Alnemri, E. S., Testa, U., Peschle, C. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401: 489-493, 1999. [PubMed: 10519553] [Full Text: https://doi.org/10.1038/46809]
de Thonel, A., Vandekerckhove, J., Lanneau, D., Selvakumar, S., Courtois, G., Hazoume, A., Brunet, M., Maurel, S., Hammann, A., Ribeil, J. A., Zermati, Y., Gabet, A. S., Boyes, J., Solary, E., Hermine, O., Garrido, C. HSP27 controls GATA-1 protein level during erythroid cell differentiation. Blood 116: 85-96, 2010. [PubMed: 20410505] [Full Text: https://doi.org/10.1182/blood-2009-09-241778]
Evans, T., Reitman, M., Felsenfeld, G. An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc. Nat. Acad. Sci. 85: 5976-5980, 1988. [PubMed: 3413070] [Full Text: https://doi.org/10.1073/pnas.85.16.5976]
Freson, K., Devriendt, K., Matthijs, G., Van Hoof, A., De Vos, R., Thys, C., Minner, K., Hoylaerts, M. F., Vermylen, J., Van Geet, C. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98: 85-92, 2001. [PubMed: 11418466] [Full Text: https://doi.org/10.1182/blood.v98.1.85]
Freson, K., Matthijs, G., Thys, C., Marien, P., Hoylaerts, M. F., Vermylen, J., Van Geet, C. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum. Molec. Genet. 11: 147-152, 2002. [PubMed: 11809723] [Full Text: https://doi.org/10.1093/hmg/11.2.147]
Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C., Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Nat. Acad. Sci. 93: 12355-12358, 1996. [PubMed: 8901585] [Full Text: https://doi.org/10.1073/pnas.93.22.12355]
Fulco, C. P., Munschauer, M., Anyoha, R., Munson, G., Grossman, S. R., Perez, E. M., Kane, M., Cleary, B., Lander, E. S., Engreitz, J. M. Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science 354: 769-773, 2016. [PubMed: 27708057] [Full Text: https://doi.org/10.1126/science.aag2445]
Gumucio, D. L., Rood, K. L., Blanchard-McQuate, K. L., Gray, T. A., Saulino, A., Collins, F. S. Interaction of Sp1 with the human gamma globin promoter: binding and transactivation of normal and mutant promoters. Blood 78: 1853-1863, 1991. [PubMed: 1912570]
Gurbuxani, S., Vyas, P., Crispino, J. D. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103: 399-406, 2004. [PubMed: 14512321] [Full Text: https://doi.org/10.1182/blood-2003-05-1556]
Harigae, H., Xu, G., Sugawara, T., Ishikawa, I., Toki, T., Ito, E. The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. (Letter) Blood 103: 3242-3243, 2004. [PubMed: 15070711] [Full Text: https://doi.org/10.1182/blood-2004-01-0016]
Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W., Zipursky, A. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101: 4301-4304, 2003. [PubMed: 12586620] [Full Text: https://doi.org/10.1182/blood-2003-01-0013]
Hollanda, L. M., Lima, C. S. P., Cunha, A. F., Albuquerque, D. M., Vassallo, J., Ozelo, M. C., Joazeiro, P. P., Saad, S. T. O., Costa, F. F. An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nature Genet. 38: 807-812, 2006. [PubMed: 16783379] [Full Text: https://doi.org/10.1038/ng1825]
Hoppe, P. S., Schwarzfischer, M., Loeffler, D., Kokkaliaris, K. D., Hilsenbeck, O., Moritz, N., Endele, M., Filipczyk, A., Gambardella, A., Ahmed, N., Etzrodt, M., Coutu, D. L., and 11 others. Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios. Nature 535: 299-302, 2016. [PubMed: 27411635] [Full Text: https://doi.org/10.1038/nature18320]
Horak, C. E., Mahajan, M. C., Luscombe, N. M., Gerstein, M., Weissman, S. M., Snyder, M. GATA-1 binding sites mapped in the beta-globin locus by using mammalian chIp-chip analysis. Proc. Nat. Acad. Sci. 99: 2924-2929, 2002. [PubMed: 11867748] [Full Text: https://doi.org/10.1073/pnas.052706999]
Kanno, H., Tani, K., Fujii, H., Iguchi-Ariga, S. M. M., Ariga, H., Kozaki, T., Miwa, S. Adenosine deaminase (ADA) overproduction associated with congenital hemolytic anemia. case report and molecular analysis. Jpn. J. Exp. Med. 58: 1-8, 1988. [PubMed: 3164080]
Klar, J., Khalfallah, A., Arzoo, P. S., Gazda, H. T., Dahl, N. Recurrent GATA1 mutations in Diamond-Blackfan anaemia. Brit. J. Haemat. 166: 949-951, 2014. [PubMed: 24766296] [Full Text: https://doi.org/10.1111/bjh.12919]
Li, Z., Godinho, F. J., Klusmann, J.-H., Garriga-Canut, M., Yu, C., Orkin, S. H. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nature Genet. 37: 613-619, 2005. [PubMed: 15895080] [Full Text: https://doi.org/10.1038/ng1566]
Lin, H. J., Han, C.-Y., Nienhuis, A. W. Functional profile of the human fetal gamma-globin gene upstream promoter region. Am. J. Hum. Genet. 51: 363-370, 1992. [PubMed: 1642236]
Liu, L., Wen, Q., Gong, R., Stankiewicz, M. J., Li, W., Guo, M., Li, L., Sun, X., Li, W., Crispino, J. D., Huang, Z. PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1 deficient megakaryocytes by activating LYN. Cell Death Dis. 5: e988, 2014. Note: Electronic Article. [PubMed: 24407241] [Full Text: https://doi.org/10.1038/cddis.2013.512]
Look, A. T. A leukemogenic twist for GATA1. Nature Genet. 32: 83-84, 2002. [PubMed: 12172549] [Full Text: https://doi.org/10.1038/ng960]
Ludwig, L. S., Gazda, H. T., Eng, J. C., Eichhorn, S. W., Thiru, P., Ghazvinian, R., George, T. I., Gotlib, J. R., Beggs, A. H., Sieff, C. A., Lodish, H. F., Lander, E. S., Sankaran, V. G. Altered translation of GATA1 in Diamond-Blackfan anemia. Nature Med. 20: 748-753, 2014. [PubMed: 24952648] [Full Text: https://doi.org/10.1038/nm.3557]
Ludwig, L. S., Lareau, C. A., Bao, E. L., Liu, N., Utsugisawa, T., Tseng, A. M., Myers, S. A., Verboon, J. M., Ulirsch, J. C., Luo, W., Muus, C., Fiorini, C., and 20 others. Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1. Blood 139: 2534-2546, 2022. Note: Erratum: Blood 141: 1094 only, 2023. [PubMed: 35030251] [Full Text: https://doi.org/10.1182/blood.2021013753]
Lyons, S. E., Lawson, N. D., Lei, L., Bennett, P. E., Weinstein, B. M., Liu, P. P. A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes. Proc. Nat. Acad. Sci. 99: 5454-5459, 2002. [PubMed: 11960002] [Full Text: https://doi.org/10.1073/pnas.082695299]
Martin, D. I., Tsai, S. F., Orkin, S. H. Increased gamma-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor. Nature 338: 435-438, 1989. [PubMed: 2467208] [Full Text: https://doi.org/10.1038/338435a0]
McDevitt, M. A., Shivdasani, R. A., Fujiwara, Y., Yang, H., Orkin, S. H. A 'knockdown' mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. Proc. Nat. Acad. Sci. 94: 6781-6785, 1997. [PubMed: 9192642] [Full Text: https://doi.org/10.1073/pnas.94.13.6781]
Mehaffey, M. G., Newton, A. L., Gandhi, M. J., Crossley, M., Drachman, J. G. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98: 2681-2688, 2001. [PubMed: 11675338] [Full Text: https://doi.org/10.1182/blood.v98.9.2681]
Mundschau, G., Gurbuxani, S., Gamis, A. S., Greene, M. E., Arceci, R. J., Crispino, J. D. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101: 4298-4300, 2003. [PubMed: 12560215] [Full Text: https://doi.org/10.1182/blood-2002-12-3904]
Neufeld, E. J., Tubman, V. N., Levine, J. E., Campagna, D. R., Monahan-Earley, R., Dvorak, A. M., Fleming, M. D. What's in a name? (Letter) Blood 110: 2771 only, 2007.
Nichols, K. E., Crispino, J. D., Poncz, M., White, J. G., Orkin, S. H., Maris, J. M., Weiss, M. J. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24: 266-270, 2000. [PubMed: 10700180] [Full Text: https://doi.org/10.1038/73480]
Ogura, H., Yamamoto, T., Utsugisawa, T., Aoki, T., Iwasaki, T., Ondo, Y., Kawakami, T., Nakagawa, S., Ozono, S., Inada, H., Kanno, H. The novel missense mutation of GATA1 caused red cell adenosine deaminase overproduction associated with congenital hemolytic anemia. (Abstract) Blood 128: 400, 2016.
Pabst, T., Mueller, B. U., Zhang, P., Radomska, H. S., Narravula, S., Schnittger, S., Behre, G., Hiddemann, W., Tenen, D. G. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBP-alpha), in acute myeloid leukemia. Nature Genet. 27: 263-270, 2001. [PubMed: 11242107] [Full Text: https://doi.org/10.1038/85820]
Parrella, S., Aspesi, A., Quarello, P., Garelli, E., Pavesi, E., Carando, A., Nardi, M., Ellis, S. R., Ramenghi, U., Dianzani, I. Loss of GATA-1 full length as a cause of Diamond-Blackfan anemia phenotype. Pediat. Blood Cancer 61: 1319-1321, 2014. [PubMed: 24453067] [Full Text: https://doi.org/10.1002/pbc.24944]
Phillips, J. D., Steensma, D. P., Pulsipher, M. A., Spangrude, G. J., Kushner, J. P. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109: 2618-2621, 2007. [PubMed: 17148589] [Full Text: https://doi.org/10.1182/blood-2006-06-022848]
Ribeil, J.-A., Zermati, Y., Vandekerckhove, J., Cathelin, S., Kersual, J., Dussiot, M., Coulon, S., Moura, I. C., Zeuner, A., Kirkegaard-Sorensen, T., Varet, B., Solary, E., Garrido, C., Hermine, O. Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445: 102-105, 2007. [PubMed: 17167422] [Full Text: https://doi.org/10.1038/nature05378]
Sankaran, V. G., Ghazvinian, R., Do, R., Thiru, P., Vergilio, J.-A., Beggs, A. H., Sieff, C. A., Orkin, S. H., Nathan, D. G., Lander, E. S., Gazda, H. T. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J. Clin. Invest. 122: 2439-2443, 2012. [PubMed: 22706301] [Full Text: https://doi.org/10.1172/JCI63597]
Shimizu, R., Ohneda, K., Engel, J. D., Trainor, C. D., Yamamoto, M. Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia. Blood 103: 2560-2567, 2004. [PubMed: 14656885] [Full Text: https://doi.org/10.1182/blood-2003-07-2514]
Shivdasani, R. A., Fujiwara, Y., McDevitt, M. A., Orkin, S. H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16: 3965-3973, 1997. [PubMed: 9233806] [Full Text: https://doi.org/10.1093/emboj/16.13.3965]
Stumpf, M., Waskow, C., Krotschel, M., van Essen, D., Rodriguez, P., Zhang, X., Guyot, B., Roeder, R. G., Borggrefe, T. The mediator complex functions as a coactivator for GATA-1 in erythropoiesis via subunit Med1/TRAP220. Proc. Nat. Acad. Sci. 103: 18504-18509, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 104: 1442 only, 2007. [PubMed: 17132730] [Full Text: https://doi.org/10.1073/pnas.0604494103]
Taub, J. W., Mundschau, G., Ge, Y., Poulik, J. M., Qureshi, F., Jensen, T., James, S. J., Matherly, L. H., Wechsler, J., Crispino, J. D. Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. (Letter) Blood 104: 1588-1589, 2004. [PubMed: 15317736] [Full Text: https://doi.org/10.1182/blood-2004-04-1563]
Thompson, A. R., Wood, W. G., Stamatoyannopoulos, G. X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis. Blood 50: 303-316, 1977. [PubMed: 871527]
Trainor, C. D., Evans, T., Felsenfeld, G., Boguski, M. S. Structure and evolution of a human erythroid transcription factor. Nature 343: 92-96, 1990. [PubMed: 2104960] [Full Text: https://doi.org/10.1038/343092a0]
Tubman, V. N., Levine, J. E., Campagna, D. R., Monahan-Earley, R., Dvorak, A. M., Neufeld, E. J., Fleming, M. D. X-linked gray platelet syndrome due to a GATA1 arg216gln mutation. Blood 109: 3297-3299, 2007. [PubMed: 17209061] [Full Text: https://doi.org/10.1182/blood-2006-02-004101]
Wall, L., deBoer, E., Grosveld, F. The human beta-globin gene 3-prime enhancer contains multiple binding sites for an erythroid-specific protein. Genes Dev. 2: 1089-1100, 1988. [PubMed: 2461328] [Full Text: https://doi.org/10.1101/gad.2.9.1089]
Wechsler, J., Greene, M., McDevitt, M. A., Anastasi, J., Karp, J. E., Le Beau, M. M., Crispino, J. D. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nature Genet. 32: 148-152, 2002. [PubMed: 12172547] [Full Text: https://doi.org/10.1038/ng955]
Whyatt, D., Lindeboom, F., Karis, A., Ferreira, R., Milot, E., Hendriks, R., de Bruijn, M., Langeveld, A., Gribnau, J., Grosveld, F., Philipsen, S. An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells. Nature 406: 519-524, 2000. [PubMed: 10952313] [Full Text: https://doi.org/10.1038/35020086]
Yu, C., Niakan, K. K., Matsushita, M., Stamatoyannopoulos, G., Orkin, S. H., Raskind, W. H. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100: 2040-2045, 2002. [PubMed: 12200364] [Full Text: https://doi.org/10.1182/blood-2002-02-0387]
Yu, L., Ji, W., Zhang, H., Renda, M. J., He, Y., Lin, S., Cheng, E., Chen, H., Krause, D. S., Min, W. SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J. Exp. Med. 207: 1183-1195, 2010. [PubMed: 20457756] [Full Text: https://doi.org/10.1084/jem.20092215]
Zon, L. I., Tsai, S.-F., Burgess, S., Matsudaira, P., Bruns, G. A. P., Orkin, S. H. The major human erythroid DNA-binding protein (GF-1): primary sequence and localization of the gene to the X chromosome. Proc. Nat. Acad. Sci. 87: 668-672, 1990. [PubMed: 2300555] [Full Text: https://doi.org/10.1073/pnas.87.2.668]