title: Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1.
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 differentiation. 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 fingers. 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; refs 9-12). 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Nichols
authors.forename: J D
authors.initials: JD
authors.lastname: Crispino
authors.forename: M
authors.initials: M
authors.lastname: Poncz
authors.forename: J G
authors.initials: JG
authors.lastname: White
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.forename: J M
authors.initials: JM
authors.lastname: Maris
authors.forename: M J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics*; D002648:Child; D016384:Consensus Sequence; D003456:Cryptorchidism / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D050982:GATA1 Transcription Factor; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013921:Thrombocytopenia / Q000151:congenital / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014960:X Chromosome / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors