GATA1

The human GATA1 gene is located on the short (i.e. "p") arm of the X chromosome at position 11.23. It is 7.74 kilobases in length, consists of 6 exons, and codes for a full-length protein, GATA1, of 414 amino acids as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids. GATA1 codes for two zinc finger structural motifs, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1. == GATA1 proteins ==

In both GATA1 and GATA1-S, C-ZnF (i.e. C-terminus zinc finger) binds to DNA-specific nucleic acid sequences sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e. N-terminus zinc fingers) interacts with an essential transcription factor-regulating nuclear protein, FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of Gata1, knockout of the mouse gene for FOG1, Zfpm1, causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes, Mi-2/NuRD complex (a chromatin remodeler) and CTBP1 (a histone deacetylase) and three gene expression-regulating proteins, SET8 (a GATA1-inhibiting histone methyltransferase), BRG1 (a transcription activator), and Mediator (a transcription co-activator). Other interactions include those with: BRD3 (remodels DNA nucleosomes), BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility), HDAC1 (a histone deacetylase), LMO2 (regulator of erythrocyte development), ZBTB16 (transcription factor regulating cell cycle progression), TAL1 (a transcription factor), FOG2 (a transcription factor regulator), and GATA2 (Displacement of GATA2 by GATA1, i.e. the "GATA switch", at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans). GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans. == Physiology and Pathology ==

GATA1 was first described as a transcription factor that activates the hemoglobin B gene in the red blood cell precursors of chickens. Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g. erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew. GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their cytoskeleton and that make enzymes necessary for the biosynthesis of hemoglobins and heme, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells. The clinical features associated with inactivating GATA1 mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors. First, inactivating mutations in GATA1 cause X-linked recessive diseases. Males, with only one GATA1 gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation is dominant negative, i.e. inhibiting the good gene's function. Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity. Third, inactivating GATA1 mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus thalassemia-type and porphyria-type symptoms. Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example, GATA1-inactivating mutations in individuals with the extra chromosome 21 of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results in acute megakaryoblastic leukemia. == Genetic disorders ==

GATA1 gene mutations are associated with the development of various genetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with its GATA1 gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead to X-linked diseases occurring predominantly in males. Diamond–Blackfan anemia Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in infancy or, less commonly, later childhood as aplastic anemia and the circulation of abnormally enlarged red blood cells. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of affected individuals have various birth defects. • V205M: familial disease characterized by severe anemia in fetuses and newborns; bone marrow has increased numbers of malformed platelet and red blood cell precursors. • G208S and D218G: familial disease characterized by severe bleeding, reduced number of circulating platelets which are malformed (i.e. enlarged), and mild anemia. • D218Y: familial disease similar to but more severe that the disease cause by G209S and D218G mutations. • R216W: characterized by a beta thalassemia-type disease, i.e. microcytic anemia, absence of hemoglobin B, and hereditary persistence of fetal hemoglobin; symptoms of congenital erythropoietic porphyria; mild to moderately severe thrombocytopenia with features of the gray platelet syndrome. • R216Q: familial disease characterized by mild anemia with features of heterozygous rather than homozygous (i.e. overt) beta thalassemia; mild thrombocytopenia with features of the gray platelet syndrome. • G208R: disease characterized by mild anemia and severe thrombocytopenia with malformed erythroblasts and megakaryoblasts in the bone marrow. Structural features of these cells were similar to those observed in congenital dyserythropoietic anemia. • -183G>A: rare Single-nucleotide polymorphism (rs113966884) in which the nucleotide adenine replaces guanine in DNA at the position 183 nucleotides upstream of the start of GATA1; disorder characterized as mild anemia with structural features in bone marrow red cell precursors similar to those observed in congenital dyserythropoietic anemia. The Gray platelet syndrome is a rare congenital bleeding disorder caused by reductions or absence of alpha-granules in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in the NBEAL2 gene located on human chromosome 3 at position p21. In these cases, the syndrome follows autosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in neutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease of Arc syndrome caused by mutations in either the VPS33B (on human chromosome 15 at q26) or VIPAS39 (on chromosome 14 at q34); the autosomal dominant disease of GFI1B-related syndrome caused by mutations in GFI1B (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused by NBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e. thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from the NBEAL2-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, a thalassemia-like disorder due to unbalanced hemoglobin production, and/or a porphyria-like disorder. Given these differences, the GATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome. == GATA1 in myelofibrosis ==

Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow, extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformed megakaryocytes in the bone marrow. Ultimately, the disease may progress to leukemia. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in translating GATA1 mRNA into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to its leukemic transformation. == References ==