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

Haematopoietic development is regulated by nuclear protein complexes that c oordinate lineage-specific patterns of gene expression. Targeted mutagenesi s in embryonic stem cells and mice has revealed roles for the X-linked gene Gata1 in erythrocyte and megakaryocyte differentiation(1-4), GATA-1 is the founding member of a family of DNA-binding proteins that recognize the mot if WGATAR through a conserved multifunctional domain consisting of two C4-t ype zinc fingers(5-8). Here we describe a family with X-linked dyserythropo ietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1. This highly conserved valine is necessa ry for interaction of the amino-terminal zinc finger of GATA-1 with its ess ential cofactor, FOG-1 (for friend of GATA-1; refs 9-12). We show that the V205M mutation abrogates the interaction between Gata-1 and Fog-1, inhibiti ng the ability of Gata-1 to rescue erythroid differentiation in an erythroi d cell line deficient for Gata-1 (G1E). Our findings underscore the importa nce of FOG-1:Gata-1 associations in both megakaryocyte and erythroid develo pment, and suggest that other X-linked anaemias or thrombocytopenias may be caused by defects in GATA1.