Dyserythropoietic Anemia and Thrombocytopenia due to a Novel Mutation in GATA-1

Abstract

Hematopoiesis is a complex process regulated by nuclear proteins that coordinate lineage-specific patterns of gene expression. Targeted mutagenesis has revealed critical roles for the X-linked transcription factor GATA-1 in erythrocyte and megakaryocyte differentiation. GATA-1 has two zinc fingers essential for normal function. The C-terminal finger is necessary for DNA binding. The N-terminal finger mediates interaction with FOG-1, a cofactor for GATA-1. Mutations in the N-terminal zinc finger of GATA-1 result in abnormal hematopoiesis. Here we report a family with a novel single base mutation that results in an amino acid substitution (Gly208Arg) within the highly conserved portion of the GATA-1 N-terminal finger domain, leading to dyserythropoietic anemia and macrothrombocytopenia. Another mutation described at the same codon (208) has been found to be associated with thrombocytopenia only. Our data support and extend the effect of the amino acid substitution at codon 208 on GATA-1 function not only regarding megakaryocyte but also regarding erythroid development.

GATA1 erythroid-specific regulation of SEC23B expression and its implication in the pathogenesis of congenital dyserythropoietic anemia type II

“…The clinical data affecting both erythroid and megakaryocytic lines prompted us to perform sequencing analysis of both GATA1 and SEC23B. We identified the causative mutation of X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA) GATA1-p.G208R, 9 but no causative mutations in SEC23B gene.…”

Novel GATA1 mutation in residue D218 leads to macrothrombocytopenia and clinical bleeding problems

“…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.…”

“…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.…”

“…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.…”

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

“…Another base mutation that results in Gly208Arg substitution within the highly conserved portion of the Nterminal finger domain has been associated to dyserythropoietic anemia and macrothrombocytopenia. 83 Recently, alteration in the erythroid transcriptional factor KLF1 has been associated to CDA type IV 84 in the case of 2 patients with a hitherto unclassified CDA in whom the Glu325Lys missense mutation in KLF1 was identified ( Figure 1). Patients showed severe anemia at birth and required repeated transfusion during childhood, persistent expression of ε and ζ embryonic globin, an HbF level of 40%, novel intra-erythroblastic and intra-erythrocytic inclusions, and deficiency of erythroid proteins CD44 and aquaporin 1.…”