Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1G208R germline mutation

Kratz, CP; Niemeyer, Charlotte M.; Karow, Axel; Volz-Fleckenstein, Marlene; Schmitt‐Gräff, Annette; Strahm, Brigitte

doi:10.1038/sj.leu.2404904

Cited by 17 publications

(12 citation statements)

References 10 publications

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“…These mutations most commonly introduce amino acid replacements into the Nf, affecting its ability to bind FOG1, TAL1, and associated proteins (discussed below) or DNA. 10,[16][17][18][19][20] Affected patients exhibit a range of distinct and overlapping phenotypes including CDA, thrombocytopenia, erythropoietic porphyria, thalassemia, and Gray platelet syndrome. Recently, a mutation in the C terminus of GATA1 was identified in a family with X-linked Lutheran (a-b-) blood group phenotype (absent expression of the Lutheran glycoprotein) and mild macrothrombocytopenia.…”

Section: Cis Element Mutationsmentioning

confidence: 99%

Erythro-megakaryocytic transcription factors associated with hereditary anemia

Crispino

Weiss

2014

Blood

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Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.

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Section: Cis Element Mutationsmentioning

confidence: 99%

Erythro-megakaryocytic transcription factors associated with hereditary anemia

Crispino

Weiss

2014

Blood

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“…19,25,26 Missense mutations in the GATA1 NF cause distinct forms of congenital anemia and thrombocytopenia. Although similarly located, the 7 reported mutations produce a wide spectrum of phenotypes [27][28][29][30][31][32][33][34][35][36][37][38] (for review, see Ciovacco et al 39 ) (supplemental Table 1, available on the Blood website). Clinical severity depends on the site and type of substitution, and different substitutions at the same amino acid position produce disparate phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Analysis of disease-causing GATA1 mutations in murine gene complementation systems

Campbell

Wilkinson-White

Mackay

et al. 2013

Blood

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Missense mutations in transcription factor GATA1 underlie a spectrum of congenital red blood cell and platelet disorders. We investigated how these alterations cause distinct clinical phenotypes by combining structural, biochemical, and genomic approaches with gene complementation systems that examine GATA1 function in biologically relevant cellular contexts. Substitutions that disrupt FOG1 cofactor binding impair both gene activation and repression and are associated with pronounced clinical phenotypes. Moreover, clinical severity correlates with the degree of FOG1 disruption. Surprisingly, 2 mutations shown to impair DNA binding of GATA1 in vitro did not measurably affect in vivo target gene occupancy. Rather, one of these disrupted binding to the TAL1 complex, implicating it in diseases caused by GATA1 mutations. Diminished TAL1 complex recruitment mainly impairs transcriptional activation and is linked to relatively mild disease. Notably, different substitutions at the same amino acid can selectively inhibit TAL1 complex or FOG1 binding, producing distinct cellular and clinical phenotypes. The structure-function relationships elucidated here were not predicted by prior in vitro or computational studies. Thus, our findings uncover novel disease mechanisms underlying GATA1 mutations and highlight the power of gene complementation assays for elucidating the molecular basis of genetic diseases. (Blood. 2013;121(26):5218-5227) IntroductionErythrocyte and megakaryocyte development are under the control of transcription factor GATA1.1,2 GATA1 promotes differentiation by activating all known erythroid-and megakaryocytespecific genes and silencing genes associated with the immature, proliferative state and alternative lineages (for review, see Ferreira et al 3 ). GATA1 contains 2 highly conserved zinc finger (ZF) domains. The C-terminal ZF primarily binds to the sequence (A/T)GATA(A/G) while the N-terminal ZF (NF) stabilizes DNA interactions by contacting noncanonical GATC and palindromic ATC(A/T)GATA(A/G) motifs. [4][5][6] The NF also binds coregulators, including the multi-ZF protein FOG1.7 Like GATA1, FOG1 is required for erythroid and megakaryocyte development, and disrupting the GATA1-FOG1 interaction impairs maturation of these lineages. [8][9][10] Activation and repression of most GATA1-regulated genes requires FOG1, 11,12 as does silencing of mast cell-specific genes.13-15 FOG1 also modulates GATA1 chromatin occupancy at a subset of genomic sites. [15][16][17] Additionally, the TAL1 complex, composed of TAL1, E2A, LMO2, and Ldb1, interacts via LMO2 with the GATA1 NF.18,19 TAL1, LMO2, and Ldb1 are essential for erythrocyte and megakaryocyte differentiation.20-22 TAL1 complex recruitment occurs predominantly at GATA1-activated genes and tends to be depleted at sites where GATA1 functions as a repressor. 23,24 The distinct interaction surfaces of GATA1 that contact DNA, FOG1, and LMO2 have been defined previously. 19,25,26 Missense mutations in the GATA1 NF cause distinct forms of congenital anemia and thrombocy...

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“…The PFA100 closure time with collagen/epinephrine for patient III:4 was prolonged (4300 s; nl: 82-142 s) while normal with collagen/ADP. X-linked macrothrombocytopenia with platelet dysfunction has been described by others and us for patients with mutations in the gene for the transcription factor GATA1 [1][2][3][4][5][6][7][8][9][10]. The GATA family of nuclear regulatory proteins serves as a prototype for the action of lineage-restricted transcription factors.…”

Section: To the Editormentioning

confidence: 98%

“…Remarkably since its first description in 2001, still only a limited number of families are presently reported with germline GATA1 missense mutations and these presented with closely related but still somewhat altered hematological disorders. They comprise severe dyserythropoietic anemia with macrothrombocytopenia (V205M, G208R, and D218Y), macrothrombocytopenia with mild dyserythropoietic features (G208S, D218G), macrothrombocytopenia with mild b-thalassemia (R216Q), and congenital erythropoietic porphyria (R216W) [1][2][3][4][5][6][7][8][9][10]. Figure 1(B) shows the position of these mutations that are all present in the N-terminal zinc finger of GATA1.…”

Section: To the Editormentioning

confidence: 99%

“…Males with these mutations have enlarged platelets with a paucity of alpha granules and a reduced function. Some patients also present with splenomegaly [7,9] or myelodysplasia with marked organomegaly [10], likely due to ineffective and consequential extramedullary hematopoiesis. Genotype-phenotype correlations are hampered by the low numbers of families with a GATA1 mutation to date, with only two mutations (R216Q [6][7][8] and G208R [5,10]) being identified in more than one family.…”

Section: To the Editormentioning

confidence: 99%

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