View source for GATA1

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{{Short description|Protein-coding gene in humans}}
{{Infobox_gene}}
'''GATA-binding factor 1''' or '''GATA-1''' (also termed '''Erythroid transcription factor''') is the founding member of the [[GATA transcription factor|GATA family of transcription factors]]. This [[protein]]  is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the ''GATA1'' and ''Gata1'' genes, respectively. These genes are located on the [[X chromosome]] in both species.<ref name="pmid23838521">{{cite journal | vauthors = Katsumura KR, DeVilbiss AW, Pope NJ, Johnson KD, Bresnick EH | title = Transcriptional mechanisms underlying hemoglobin synthesis | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 9 | pages = a015412 | date = September 2013 | pmid = 23838521 | pmc = 3753722 | doi = 10.1101/cshperspect.a015412 }}</ref><ref name="pmid1999341">{{cite journal | vauthors = Caiulo A, Nicolis S, Bianchi P, Zuffardi O, Bardoni B, Maraschio P, Ottolenghi S, Camerino G, Giglioni B | title = Mapping the gene encoding the human erythroid transcriptional factor NFE1-GF1 to Xp11.23 | journal = Human Genetics | volume = 86 | issue = 4 | pages = 388–90 | date = Feb 1991 | pmid = 1999341 | doi = 10.1007/bf00201840 | s2cid = 20747016 }}</ref>
GATA1 regulates the [[Gene expression|expression]] (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the [[Erythropoiesis|maturation]] of precursor cells, e.g. [[erythroblast]]s, to red blood cells and stimulating these cells to erect their [[cytoskeleton]] and [[biosynthesis|biosynthesize]] their oxygen-carrying components viz., [[hemoglobin]] and [[heme]]. GATA1 plays a similarly critical role in the maturation of blood [[platelets]] from [[megakaryoblast]]s, [[promegakaryocyte]]s, and [[megakaryocyte]]s; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood.<ref name="pmid23838521"/><ref name="pmid26186939">{{cite journal | vauthors = Gruber TA, Downing JR | title = The biology of pediatric acute megakaryoblastic leukemia | journal = Blood | volume = 126 | issue = 8 | pages = 943–9 | date = August 2015 | pmid = 26186939 | pmc = 4551356 | doi = 10.1182/blood-2015-05-567859 }}</ref>
In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, [[Mutations#By effect on function|inactivating mutations]] in the ''GATA1'' gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause [[Sex linkage|X chromosome-linked]] [[anemic]] and/or [[bleeding disorders|bleeding diseases]] due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include [[Down syndrome#Cancer|transient myeloproliferative disorder]] occurring in Down syndrome, [[acute megakaryoblastic leukemia]] occurring in [[Down syndrome#Cancer|Down syndrome]], [[Diamond–Blackfan anemia]], and various combined [[anemia]]-[[thrombocytopenia]] syndromes including a [[gray platelet syndrome]]-type disorder.<ref name="pmid28566565">{{cite journal | vauthors = Fujiwara T | title = GATA Transcription Factors: Basic Principles and Related Human Disorders | journal = The Tohoku Journal of Experimental Medicine | volume = 242 | issue = 2 | pages = 83–91 | date = June 2017 | pmid = 28566565 | doi = 10.1620/tjem.242.83 | doi-access = free }}</ref><ref>{{cite web | title = Entrez Gene: GATA1 GATA binding protein 1 (globin transcription factor 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2623}}</ref><ref name="pmid29081386">{{cite journal | vauthors = Da Costa L, O'Donohue MF, van Dooijeweert B, Albrecht K, Unal S, Ramenghi U, Leblanc T, Dianzani I, Tamary H, Bartels M, Gleizes PE, Wlodarski M, MacInnes AW | title = Molecular approaches to diagnose Diamond–Blackfan anemia: The EuroDBA experience | journal = European Journal of Medical Genetics | volume = 61| issue = 11| pages = 664–673| date = October 2017 | pmid = 29081386 | doi = 10.1016/j.ejmg.2017.10.017 | doi-access = free | hdl = 2318/1676982 | hdl-access = free }}</ref>
Reduced levels of GATA1 due to reductions in the translation of GATA1 [[mRNA]] into its transcription factor product are associated with promoting the progression of [[myelofibrosis]], i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and [[extramedullary hematopoiesis]], i.e. the extension of blood cell-forming cells to sites outside of the [[bone marrow]].<ref name="pmid20458749">{{cite journal | vauthors = Verrucci M, Pancrazzi A, Aracil M, Martelli F, Guglielmelli P, Zingariello M, Ghinassi B, D'Amore E, Jimeno J, Vannucchi AM, Migliaccio AR | title = CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin | journal = Journal of Cellular Physiology | volume = 225 | issue = 2 | pages = 490–9 | date = November 2010 | pmid = 20458749 | pmc = 3780594 | doi = 10.1002/jcp.22228 }}</ref><ref name="pmid29562644">{{cite journal | vauthors = Song MK, Park BB, Uhm JE | title = Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis | journal = International Journal of Molecular Sciences | volume = 19 | issue = 3 | pages = 898| date = March 2018 | pmid = 29562644 | pmc = 5877759 | doi = 10.3390/ijms19030898 | doi-access = free }}</ref>
== Gene ==
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 [[Base pair#Length measurements|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.<ref>{{Cite web | url=https://www.ncbi.nlm.nih.gov/gene/2623 |title = GATA1 GATA binding protein 1 &#91;Homo sapiens (human)&#93; - Gene - NCBI}}</ref><ref>{{Cite web | url=http://genatlas.medecine.univ-paris5.fr/fiche.php?onglet=2&n=5186 |title = Genatlas sheet}}</ref><ref name="pmid27235756">{{cite journal | vauthors = Shimizu R, Yamamoto M | title = GATA-related hematologic disorders | journal = Experimental Hematology | volume = 44 | issue = 8 | pages = 696–705 | date = August 2016 | pmid = 27235756 | doi = 10.1016/j.exphem.2016.05.010 | doi-access = free }}</ref> ''GATA1'' codes for two [[zinc finger]] [[structural motif]]s, 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.<ref name="pmid28566565"/><ref name="pmid27235756"/>
Studies in ''Gata1''-[[knockout mice]], i.e. mice lacking the ''Gata1'' gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly [[red blood cell]]s and [[platelets]] but also [[eosinophil]]s, [[basophil]]s, [[mast cell]]s, and [[dendritic cell]]s. The knock-out mice die by day 11.5 of their [[embryonic development]] due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of [[platelet]]s. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet [[precursor cell]]s. Studies using mice depleted of their ''Gata1'' gene during adulthood show that: '''1)''' Gata1 is required for the stimulation of [[erythropoiesis]] (i.e. increase in red blood cell formation) in response to stress and '''2)''' ''Gata1''-deficient adult mice invariably develop a form of [[myelofibrosis]].<ref name="pmid28179280">{{cite journal | vauthors = Crispino JD, Horwitz MS | title = GATA factor mutations in hematologic disease | journal = Blood | volume = 129 | issue = 15 | pages = 2103–2110 | date = April 2017 | pmid = 28179280 | pmc = 5391620 | doi = 10.1182/blood-2016-09-687889 }}</ref><ref name="pmid28179282">{{cite journal | vauthors = Katsumura KR, Bresnick EH | title = The GATA factor revolution in hematology | journal = Blood | volume = 129 | issue = 15 | pages = 2092–2102 | date = April 2017 | pmid = 28179282 | pmc = 5391619 | doi = 10.1182/blood-2016-09-687871 }}</ref>
== GATA1 proteins ==
In both GATA1 and GATA1-S, C-ZnF (i.e. [[C-terminus]] zinc finger) binds to DNA-specific [[nucleic acid sequence]]s 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, [[ZFPM1|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|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 remodeling|chromatin remodeler]]) and [[CTBP1]] (a [[histone deacetylase]]) and three gene expression-regulating proteins, [[KMT5A|SET8]] (a GATA1-inhibiting [[histone methyltransferase]]), [[SMARCA4|BRG1]] (a [[transcription activator]]), and [[Mediator (coactivator)|Mediator]] (a [[Coactivator (genetics)|transcription co-activator]]). Other interactions include those with: [[BRD3]] (remodels DNA [[nucleosome]]s),<ref name="Lamonica_2011">{{cite journal | vauthors = Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA | title = Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 22 | date = May 2011 | pmid = 21536911 | doi = 10.1073/pnas.1102140108 | pages=E159-68 | pmc=3107332| doi-access = free }}</ref><ref>{{cite journal | vauthors = Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP | title = Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3 | journal = Molecular and Cellular Biology | volume = 31 | issue = 13 | date = Jul 2011 | pmid = 21555453 | doi = 10.1128/MCB.05413-11 | pages=2632–40 | pmc=3133386}}</ref><ref>{{cite journal | vauthors = Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA | title = Functions of BET proteins in erythroid gene expression | journal = Blood | date = Feb 2015 | pmid = 25696920 | doi = 10.1182/blood-2014-10-607309 | volume=125 | issue = 18 | pages=2825–34 | pmc=4424630}},</ref> [[BRD4]] (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility),<ref name="Lamonica_2011" /> [[FLI1]] (a transcription factor that blocks erythroid differentiation),<ref name="pmid2724402">{{cite journal | vauthors = Lahiri K, Dole MG, Vidwans AS, Kamat J, Kandoth P | title = Acute glomerulonephritis | journal = Journal of Tropical Pediatrics | volume = 35 | issue = 2 | pages = 92 | date = Apr 1989 | pmid = 2724402 | doi = 10.1093/tropej/35.2.92 }}</ref><ref name="pmid12556498">{{cite journal | vauthors = Starck J, Cohet N, Gonnet C, Sarrazin S, Doubeikovskaia Z, Doubeikovski A, Verger A, Duterque-Coquillaud M, Morle F | title = Functional cross-antagonism between transcription factors FLI-1 and EKLF | journal = Molecular and Cellular Biology | volume = 23 | issue = 4 | pages = 1390–402 | date = Feb 2003 | pmid = 12556498 | pmc = 141137 | doi = 10.1128/MCB.23.4.1390-1402.2003 }}</ref> [[HDAC1]] (a [[histone deacetylase]]),<ref name="pmid14668799">{{cite journal | vauthors = Watamoto K, Towatari M, Ozawa Y, Miyata Y, Okamoto M, Abe A, Naoe T, Saito H | title = Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation | journal = Oncogene | volume = 22 | issue = 57 | pages = 9176–84 | date = Dec 2003 | pmid = 14668799 | doi = 10.1038/sj.onc.1206902 | s2cid = 24491249 | doi-access =  }}</ref> [[LMO2]] (regulator of erythrocyte development),<ref name="Osada_1995">{{cite journal | vauthors = Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH | title = Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9585–9 | date = Oct 1995 | pmid = 7568177 | pmc = 40846 | doi = 10.1073/pnas.92.21.9585 | bibcode = 1995PNAS...92.9585O | doi-access = free }}</ref> [[Zinc finger and BTB domain-containing protein 16|ZBTB16]] (transcription factor regulating [[cell cycle]] progression),<ref name="pmid12242665">{{cite journal | vauthors = Labbaye C, Quaranta MT, Pagliuca A, Militi S, Licht JD, Testa U, Peschle C | title = PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein | journal = Oncogene | volume = 21 | issue = 43 | pages = 6669–79 | date = Sep 2002 | pmid = 12242665 | doi = 10.1038/sj.onc.1205884 | doi-access = free }}</ref> [[TAL1]] (a transcription factor),<ref name="pmid16407974">{{cite journal | vauthors = Goardon N, Lambert JA, Rodriguez P, Nissaire P, Herblot S, Thibault P, Dumenil D, Strouboulis J, Romeo PH, Hoang T | title = ETO2 coordinates cellular proliferation and differentiation during erythropoiesis | journal = The EMBO Journal | volume = 25 | issue = 2 | pages = 357–66 | date = Jan 2006 | pmid = 16407974 | pmc = 1383517 | doi = 10.1038/sj.emboj.7600934 }}</ref> [[ZFPM2|FOG2]] (a transcription factor regulator),<ref name="pmid10438528">{{cite journal | vauthors = Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B | title = hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 33 | pages = 23491–8 | date = Aug 1999 | pmid = 10438528 | doi = 10.1074/jbc.274.33.23491 | doi-access = free }}</ref> 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).<ref name="pmid28179282"/><ref>{{cite journal | vauthors = Fujiwara Y, Browne CP, Cunniff K, Goff SC, Orkin SH | title = Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 22 | pages = 12355–8 | date = Oct 1996 | pmid = 8901585 | pmc = 37995 | doi=10.1073/pnas.93.22.12355| bibcode = 1996PNAS...9312355F | doi-access = free }}</ref><ref>{{cite journal | vauthors = Campbell AE, Wilkinson-White L, Mackay JP, Matthews JM, Blobel GA | title = Analysis of disease-causing GATA1 mutations in murine gene complementation systems | journal = Blood | volume = 121 | issue = 26 | pages = 5218–27 | date = Jun 2013 | pmid = 23704091 | pmc = 3695365 | doi = 10.1182/blood-2013-03-488080 }}</ref>  GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans.<ref name="pmid28179282"/>
Other types of ''GATA2'' mutations cause the over-expression of the GATA2 transcription factor. This overexpression is associated with the development of non-familial AML. Apparently, the ''GATA2'' gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease.<ref name="pmid25619630">{{cite journal | vauthors = Mir MA, Kochuparambil ST, Abraham RS, Rodriguez V, Howard M, Hsu AP, Jackson AE, Holland SM, Patnaik MM | title = Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations | journal = Cancer Medicine | volume = 4 | issue = 4 | pages = 490–9 | date = April 2015 | pmid = 25619630 | pmc = 4402062 | doi = 10.1002/cam4.384 }}</ref>
== 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.<ref>{{cite journal | vauthors = Evans T, Reitman M, Felsenfeld G | title = An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 16 | pages = 5976–80 | date = Aug 1988 | pmid = 3413070 | pmc = 281888 | doi=10.1073/pnas.85.16.5976| bibcode = 1988PNAS...85.5976E | doi-access = free }}</ref> 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. [[erythroblast]]s) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to [[Stem cell#Self-renewal|self-renew]].<ref name="ReferenceA">{{cite journal | vauthors = Welch JJ, Watts JA, Vakoc CR, Yao Y, Wang H, Hardison RC, Blobel GA, Chodosh LA, Weiss MJ | title = Global regulation of erythroid gene expression by transcription factor GATA-1 | journal = Blood | volume = 104 | issue = 10 | pages = 3136–47 | date = Nov 2004 | pmid = 15297311 | doi = 10.1182/blood-2004-04-1603 | doi-access = free }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Cheng Y, Wu W, Kumar SA, Yu D, Deng W, Tripic T, King DC, Chen KB, Zhang Y, Drautz D, Giardine B, Schuster SC, Miller W, [[Francesca Chiaromonte|Chiaromonte F]], Zhang Y, Blobel GA, Weiss MJ, Hardison RC | title = Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression | journal = Genome Research | volume = 19 | issue = 12 | pages = 2172–84 | date = Dec 2009 | pmid = 19887574 | pmc = 2792182 | doi = 10.1101/gr.098921.109 }}</ref> 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 [[hemoglobin]]s 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.<ref name="pmid23838521"/> Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This [[Thrombopoiesis|maturation]] involves the stimulation of [[megakaryoblast]]s to mature ultimately to [[megakaryocyte]]s which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets.<ref name="pmid23838521"/><ref name="pmid26186939"/>
Reduced levels of GATA1 due to defective [[translation]] of GATA1 [[mRNA]] in human megakaryocytes is associated with [[myelofibrosis]], i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow [[stromal cells]] to become fiber-secreting [[fibroblasts]] and [[osteoblasts]]. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic [[splenomegaly|enlargement]] and [[extramedullary hematopoiesis]] in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.<ref name="pmid20458749"/><ref name="pmid29562644"/><ref name="pmid29611379">{{cite journal | vauthors = Yang N, Park S, Cho MS, Lee M, Hong KS, Mun YC, Seong CM, Huh HJ, Huh J | title = GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms | journal = Annals of Laboratory Medicine | volume = 38 | issue = 4 | pages = 296–305 | date = July 2018 | pmid = 29611379 | pmc = 5895858 | doi = 10.3343/alm.2018.38.4.296 }}</ref><ref name="pmid28240607">{{cite journal | vauthors = Gilles L, Arslan AD, Marinaccio C, Wen QJ, Arya P, McNulty M, Yang Q, Zhao JC, Konstantinoff K, Lasho T, Pardanani A, Stein B, Plo I, Sundaravel S, Wickrema A, Migliaccio A, Gurbuxani S, Vainchenker W, Platanias LC, Tefferi A, Crispino JD | title = Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis | journal = The Journal of Clinical Investigation | volume = 127 | issue = 4 | pages = 1316–1320 | date = April 2017 | pmid = 28240607 | pmc = 5373858 | doi = 10.1172/JCI82905 }}</ref>
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 [[Genetic disorder#X-linked recessive|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 [[Mutation#By effect on function|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]].<ref name="pmid27235756"/><ref name="pmid22966823">{{cite journal | vauthors = Gamis AS, Smith FO | title = Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder | journal = British Journal of Haematology | volume = 159 | issue = 3 | pages = 277–87 | date = November 2012 | pmid = 22966823 | doi = 10.1111/bjh.12041 | s2cid = 37593917 | doi-access = free }}</ref>
== Genetic disorders ==
''GATA1'' gene [[mutation]]s 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 [[Sex linkage|X-linked diseases]] occurring predominantly in males.<ref name="pmid27235756"/> Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur in [[thalassemia]], [[gray platelet syndrome]], [[congenital erythropoietic porphyria]], and [[myelofibrosis]].<ref name="pmid28566565"/>
=== Down syndrome-related disorders ===
{{main|Down syndrome#Cancer}}
==== Transient myeloproliferative disorder ====
{{main|Transient myeloproliferative disease}}
Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations are [[frameshift mutation|frameshift]]s in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutations is restricted to cells bearing the trisomy 21 [[karyotype]] (i.e. extra [[chromosome 21]]) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder.<ref name="pmid22966823"/> Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarily [[megakaryoblast]]s, which often show an abnormal morphology that resembles immature [[myeloblast]]s (i.e. [[unipotent]] stem cells which differentiate into [[granulocytes]] and are the malignant proliferating cell in [[acute myeloid leukemia]]). [[Phenotype]] analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive [[blast cell]] numbers, reduced platelet and red blood cell levels, increased circulating [[white blood cell]] levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.<ref name="pmid22966823"/> The disorder is thought to develop [[Uterus|in utero]] and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a [[Clone (cell biology)|clonal]] (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a [[myelodysplastic syndrome]] disease.<ref name="pmid26186939"/><ref name="pmid28566565"/><ref name="pmid28179280"/><ref name="pmid22966823"/>
==== Acute megakaryoblastic leukemia ====
{{main|Acute megakaryoblastic leukemia}}
Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without [[Down syndrome]]. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder.  Their ''GATA1'' mutations are [[frameshift mutation|frameshift]]s in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia.<ref name="pmid26186939"/> During this 1-3 year interval, individuals accumulate multiple [[Mutation#Somatic mutations|somatic mutations]] in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the ''GATAT1'' mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including: ''[[TP53]], [[RUNX1]], [[FLT3]], [[ERG (gene)|ERG]], [[DYRK1A]], [[CHAF1B]], [[HLCS]], [[CTCF]], [[STAG2]], [[RAD21]], [[SMC3]], [[SMC1A]], [[NIPBL]], [[SUZ12]], [[PRC2]], [[JAK1]], [[JAK2]], [[JAK3]], [[Thrombopoietin receptor|MPL]], [[KRAS]], [[Neuroblastoma RAS viral oncogene homolog|NRAS]], [[SH2B3]]'',  and ''MIR125B2'' which is the gene for [[microRNA]] MiR125B2.<ref name="pmid26186939"/><ref name="pmid22867885">{{cite journal | vauthors = Seewald L, Taub JW, Maloney KW, McCabe ER | title = Acute leukemias in children with Down syndrome | journal = Molecular Genetics and Metabolism | volume = 107 | issue = 1–2 | pages = 25–30 | date = September 2012 | pmid = 22867885 | doi = 10.1016/j.ymgme.2012.07.011 }}</ref>
=== Diamond–Blackfan anemia ===
{{main|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 cell]]s. 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]].<ref name="pmid29081386"/> The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases, [[autosomal recessive]] inactivating mutations occur in any one of 20 of the 80 genes encoding [[ribosomal protein]]s. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., ''[[RPS19]], [[RPL5]], [[RPS26]], [[RPL11]], [[RPL35A]]'', and ''[[RPS24]]''.<ref name="pmid28566565"/><ref name="pmid29081386"/> However, several cases of familial Diamond–Blackfan anemia have been associated with ''GATA1'' gene mutations in the apparent absence of a mutation in ribosomal protein genes. These ''GATA1'' mutations occur in an exon 2 splice site or the [[start codon]] of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that these ''GATA1'' mutations are a cause for Diamond Blackfan anemia.<ref name="pmid28566565"/><ref name="pmid27235756"/><ref name="pmid28179280"/>
=== Combined anemia-thrombocytopenia syndromes ===
{{main|congenital dyserythropoietic anemia}}
Certain ''GATA1''-inactivatng mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. These ''GATA1'' mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=[[valine]]; M=[[methionine]]; G=[[glycine]]; S=[[serine]], D=[[aspartic acid]]; Y=[[tyrosine]], R=[[arginine]]; W=[[tryptophan]], Q=[[glutamine]]). These mutations and some key abnormalities they cause are:<ref name="pmid28566565"/><ref name="pmid28179280"/><ref name="pmid22886561">{{cite journal | vauthors = Balduini CL, Savoia A | title = Genetics of familial forms of thrombocytopenia | journal = Human Genetics | volume = 131 | issue = 12 | pages = 1821–32 | date = December 2012 | pmid = 22886561 | doi = 10.1007/s00439-012-1215-x | s2cid = 14396101 }}</ref><ref name="pmid28550189">{{cite journal | vauthors = Russo R, Andolfo I, Gambale A, De Rosa G, Manna F, Arillo A, Wandroo F, Bisconte MG, Iolascon A | title = GATA1 erythroid-specific regulation of SEC23B expression and its implication in the pathogenesis of congenital dyserythropoietic anemia type II | journal = Haematologica | volume = 102 | issue = 9 | pages = e371–e374 | date = September 2017 | pmid = 28550189 | pmc = 5685218 | doi = 10.3324/haematol.2016.162966 }}</ref>
* 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<ref>{{Cite web | url=https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=113966884&pt=1rE4MuqHtulrewqkpcs_tGJAQyAyRLUXCOF_U8H-YbhAT2s16HJ |title = Rs113966884 RefSNP Report - DBSNP - NCBI}}</ref>) in which the [[nucleotide]] [[adenine]] replaces [[guanine]] in DNA at the position 183 nucleotides upstream of the [[Start codon|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.<ref name="pmid26971401">{{cite journal | vauthors = Nurden AT, Nurden P | title = Should any genetic defect affecting α-granules in platelets be classified as gray platelet syndrome? | journal = American Journal of Hematology | volume = 91 | issue = 7 | pages = 714–8 | date = July 2016 | pmid = 26971401 | doi = 10.1002/ajh.24359 | s2cid = 27009005 | doi-access = free }}</ref><ref name="pmid22886561"/> A recent study found that GATA1 is a strong enhancer of ''NBEAL2'' expression and that the R216W and R216Q inactivating mutations in ''GATA1'' may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein.<ref name="pmid28082341">{{cite journal | vauthors = Wijgaerts A, Wittevrongel C, Thys C, Devos T, Peerlinck K, Tijssen MR, Van Geet C, Freson K | title = The transcription factor GATA1 regulates NBEAL2 expression through a long-distance enhancer | journal = Haematologica | volume = 102 | issue = 4 | pages = 695–706 | date = April 2017 | pmid = 28082341 | pmc = 5395110 | doi = 10.3324/haematol.2016.152777 }}</ref> Given these differences, the ''GATA1'' mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.<ref name="pmid26971401"/>
== GATA1 in myelofibrosis ==
{{main|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 [[Translation (biology)|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.<ref name="pmid29562644"/><ref name="pmid29611379"/><ref name="pmid28240607"/>
== References ==
{{reflist|35em}}
== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Ohneda K, Yamamoto M | title = Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage | journal = Acta Haematologica | volume = 108 | issue = 4 | pages = 237–45 | year = 2003 | pmid = 12432220 | doi = 10.1159/000065660 | s2cid = 29966039 }}
* {{cite journal | vauthors = Gurbuxani S, Vyas P, Crispino JD | title = Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome | journal = Blood | volume = 103 | issue = 2 | pages = 399–406 | date = Jan 2004 | pmid = 14512321 | doi = 10.1182/blood-2003-05-1556 | doi-access = free }}
* {{cite journal | vauthors = Muntean AG, Ge Y, Taub JW, Crispino JD | title = Transcription factor GATA-1 and Down syndrome leukemogenesis | journal = Leukemia & Lymphoma | volume = 47 | issue = 6 | pages = 986–97 | date = Jun 2006 | pmid = 16840187 | doi = 10.1080/10428190500485810 | s2cid = 12179485 }}
* {{cite journal | vauthors = Trainor CD, Evans T, Felsenfeld G, Boguski MS | title = Structure and evolution of a human erythroid transcription factor | journal = Nature | volume = 343 | issue = 6253 | pages = 92–6 | date = Jan 1990 | pmid = 2104960 | doi = 10.1038/343092a0 | bibcode = 1990Natur.343...92T | s2cid = 4339810 | url = https://zenodo.org/record/1233087 }}
* {{cite journal | vauthors = Zon LI, Tsai SF, Burgess S, Matsudaira P, Bruns GA, Orkin SH | title = The major human erythroid DNA-binding protein (GF-1): primary sequence and localization of the gene to the X chromosome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 2 | pages = 668–72 | date = Jan 1990 | pmid = 2300555 | pmc = 53326 | doi = 10.1073/pnas.87.2.668 | bibcode = 1990PNAS...87..668Z | doi-access = free }}
* {{cite journal | vauthors = Martin DI, Tsai SF, Orkin SH | title = Increased gamma-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor | journal = Nature | volume = 338 | issue = 6214 | pages = 435–8 | date = Mar 1989 | pmid = 2467208 | doi = 10.1038/338435a0 | bibcode = 1989Natur.338..435M | s2cid = 4361486 }}
* {{cite journal | vauthors = Mouthon MA, Bernard O, Mitjavila MT, Romeo PH, Vainchenker W, Mathieu-Mahul D | title = Expression of tal-1 and GATA-binding proteins during human hematopoiesis | journal = Blood | volume = 81 | issue = 3 | pages = 647–55 | date = Feb 1993 | pmid = 7678994 | doi =  10.1182/blood.V81.3.647.647| doi-access = free }}
* {{cite journal | vauthors = Zon LI, Yamaguchi Y, Yee K, Albee EA, Kimura A, Bennett JC, Orkin SH, Ackerman SJ | title = Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription | journal = Blood | volume = 81 | issue = 12 | pages = 3234–41 | date = Jun 1993 | pmid = 8507862 | doi =  10.1182/blood.V81.12.3234.3234| doi-access = free }}
* {{cite journal | vauthors = Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH | title = FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation | journal = Cell | volume = 90 | issue = 1 | pages = 109–19 | date = Jul 1997 | pmid = 9230307 | doi = 10.1016/S0092-8674(00)80318-9 | s2cid = 2085524 | doi-access = free }}
* {{cite journal | vauthors = Rekhtman N, Radparvar F, Evans T, Skoultchi AI | title = Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells | journal = Genes & Development | volume = 13 | issue = 11 | pages = 1398–411 | date = Jun 1999 | pmid = 10364157 | pmc = 316770 | doi = 10.1101/gad.13.11.1398 }}
* {{cite journal | vauthors = Freson K, Devriendt K, Matthijs G, Van Hoof A, De Vos R, Thys C, Minner K, Hoylaerts MF, Vermylen J, Van Geet C | title = Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation | journal = Blood | volume = 98 | issue = 1 | pages = 85–92 | date = Jul 2001 | pmid = 11418466 | doi = 10.1182/blood.V98.1.85 | doi-access = free }}
* {{cite journal | vauthors = Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG | title = X-linked thrombocytopenia caused by a novel mutation of GATA-1 | journal = Blood | volume = 98 | issue = 9 | pages = 2681–8 | date = Nov 2001 | pmid = 11675338 | doi = 10.1182/blood.V98.9.2681 | doi-access = free }}
* {{cite journal | vauthors = Crawford SE, Qi C, Misra P, Stellmach V, Rao MS, Engel JD, Zhu Y, Reddy JK | title = Defects of the heart, eye, and megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family of transcription factors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 5 | pages = 3585–92 | date = Feb 2002 | pmid = 11724781 | doi = 10.1074/jbc.M107995200 | doi-access = free }}
* {{cite journal | vauthors = Freson K, Matthijs G, Thys C, Mariën P, Hoylaerts MF, Vermylen J, Van Geet C | title = 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 | journal = Human Molecular Genetics | volume = 11 | issue = 2 | pages = 147–52 | date = Jan 2002 | pmid = 11809723 | doi = 10.1093/hmg/11.2.147 | url = https://lirias.kuleuven.be/bitstream/123456789/7719/1/147van+geet.pdf | doi-access = free }}
* {{cite journal | vauthors = Molete JM, Petrykowska H, Sigg M, Miller W, Hardison R | title = Functional and binding studies of HS3.2 of the beta-globin locus control region | journal = Gene | volume = 283 | issue = 1–2 | pages = 185–97 | date = Jan 2002 | pmid = 11867225 | doi = 10.1016/S0378-1119(01)00858-7 }}
* {{cite journal | vauthors = Hirasawa R, Shimizu R, Takahashi S, Osawa M, Takayanagi S, Kato Y, Onodera M, Minegishi N, Yamamoto M, Fukao K, Taniguchi H, Nakauchi H, Iwama A | title = Essential and instructive roles of GATA factors in eosinophil development | journal = The Journal of Experimental Medicine | volume = 195 | issue = 11 | pages = 1379–86 | date = Jun 2002 | pmid = 12045236 | pmc = 2193540 | doi = 10.1084/jem.20020170 }}
{{refend}}
== External links ==
* [https://www.genecards.org/cgi-bin/carddisp.pl?gene=GATA1 Genecards]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gata1 GeneReviews/NCBI/NIH/UW entry on GATA1-Related X-Linked Cytopenia]
* [http://www.dsi.univ-paris5.fr/genatlas/fiche.php?symbol=GATA1 Geneatlas] {{Webarchive|url=https://web.archive.org/web/20080410204329/http://www.dsi.univ-paris5.fr/genatlas/fiche.php?symbol=GATA1 |date=2008-04-10 }}
* [https://web.archive.org/web/20051022074613/http://www.infobiogen.fr/services/chromcancer/Genes/GATA1ID40689chXp11.html Infobiogen]
* [http://www.nextbio.com/b/home/home.nb?q=GATA1&dfsitype= Nextbio]
* {{FactorBook|GATA1}}
{{PDB Gallery|geneid=2623}}
{{Transcription factors and intracellular receptors|g2}}
[[Category:Transcription factors]]