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Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1

Nature Genetics volume 24, pages 266–270 (2000)Cite this article

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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Figure 1: Peripheral blood and bone marrow abnormalities in patients II-1 and II-2.
Figure 2: Ultrastructural abnormalities in megakaryocytes and platelets revealed by electron microscopy.
Figure 3: Mutational analysis of GATA1 in the affected pedigree.
Figure 4: Biochemical characterization of mutant V205M Gata-1.
Figure 5: Impaired function of V205M mutant Gata-1 in erythroid cells.

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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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Author notes

  1. Kim E. Nichols and John D. Crispino: These authors contributed equally to this work.

Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA

    Kim E. Nichols

  2. Division of Hematology and Oncology, Children's Hospital and Howard Hughes Medical Institute, Harvard Medical School, Boston , Massachusetts, USA

    John D. Crispino & Stuart H. Orkin

  3. Divisions of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Mortimer Poncz & Mitchell J. Weiss

  4. Divisions of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    John M. Maris

  5. Department of Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota, USA

    James G. White

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  1. Kim E. Nichols
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Correspondence to Mitchell J. Weiss.

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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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