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

• Published in: Nature genetics Vol. 24; no. 3; pp. 266 - 270
• Main Authors: Weiss, Mitchell J, Nichols, Kim E, Crispino, John D, Poncz, Mortimer, White, James G, Orkin, Stuart H, Maris, John M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.03.2000
• Subjects: Adult; Amino Acid Sequence; Amino Acid Substitution; Amino acids; Anemia, Dyserythropoietic, Congenital - genetics; Biological and medical sciences; Child; Consensus Sequence; Cryptorchidism - genetics; Deoxyribonucleic acid; Diagnosis; DNA; DNA binding proteins; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Erythrocytes; Erythroid-Specific DNA-Binding Factors; Familial dyserythropoietic anemia; Female; GATA-1 gene; GATA1 Transcription Factor; Gene mutations; Genetic aspects; Hematologic and hematopoietic diseases; Hematopoiesis - genetics; Humans; Identification and classification; Infant, Newborn; Male; Medical sciences; Models, Molecular; Molecular Sequence Data; Mutation; Other diseases. Hematologic involvement in other diseases; Pedigree; Physiological aspects; Point Mutation; Protein Structure, Tertiary; Recombinant Fusion Proteins - genetics; Risk factors; Stem cells; Thrombocytopenia; Thrombocytopenia - congenital; Thrombocytopenia - genetics; Transcription Factors - chemistry; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - physiology; X Chromosome - genetics; Zinc; Zinc Fingers - genetics; United States; Genetic mapping; Human; Thrombocytopenia; Linkage; Dyserythropoietic anemia; Family study; DNA binding protein; Molecular interaction; Hemopathy; Genetic disease; Platelet; Hematopoiesis; X-Chromosome; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/73480

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). 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.