Nature Genetics
24, 266 - 270 (2000)
doi:10.1038/73480
Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited
mutation in GATA1Kim E. Nichols1, 6, John D. Crispino2, 6, Mortimer Poncz3, James G. White5, Stuart H. Orkin2, John M. Maris4
& Mitchell J. Weiss31
Massachusetts General Hospital Cancer Center,
Charlestown, Massachusetts, USA. 2
Division of Hematology and Oncology, Children's Hospital
and Howard Hughes Medical Institute, Harvard Medical School, Boston
, Massachusetts, USA. 3
Divisions of Hematology, Children's Hospital of Philadelphia
, Philadelphia, Pennsylvania, USA. 4
Divisions of Oncology, Children's Hospital of Philadelphia
, Philadelphia, Pennsylvania, USA. 5
Department of Laboratory Medicine, University of Minnesota
, Minneapolis, Minnesota, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Mitchell J. Weiss weissmi@email.chop.edu.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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