Abstract
Haematopoietic development is regulated by nuclear protein complexes that coordinate lineage-specific patterns of gene expression. Targeted mutagenesis in embryonic stem cells and mice has revealed roles for the X-linked gene Gata1 in erythrocyte and megakaryocyte differentiation1,2,3,4. GATA-1 is the founding member of a family of DNA-binding proteins that recognize the motif WGATAR through a conserved multifunctional domain consisting of two C4-type zinc fingers5,6,7,8. Here we describe a family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1. This highly conserved valine is necessary for interaction of the amino-terminal zinc finger of GATA-1 with its essential cofactor, FOG-1 (for friend of GATA-1; refs9,10,11,12). We show that the V205M mutation abrogates the interaction between Gata-1 and Fog-1, inhibiting the ability of Gata-1 to rescue erythroid differentiation in an erythroid cell line deficient for Gata-1 (G1E). Our findings underscore the importance of FOG-1:Gata-1 associations in both megakaryocyte and erythroid development, and suggest that other X-linked anaemias or thrombocytopenias may be caused by defects in GATA1.
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Acknowledgements
We thank Y. Fujiwara, E. Neufeld and S. McKenzie for helpful insights and discussions; D. Haber for assistance with DNA sequencing and review of the manuscript; and J. Mackay and M. Crossley for insightful discussions and providing data on the three-dimensional structure of the GATA-1 N-terminal zinc finger. This work was supported in part by NIH grants AI K11AI01331-05 (K.E.N.), R01 CA78545 (J.M.M.) and HL40387 (M.P.).
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Nichols, K., Crispino, J., Poncz, M. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 24, 266–270 (2000). https://doi.org/10.1038/73480
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DOI: https://doi.org/10.1038/73480
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