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PMID:10700180

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Citation

Nichols, KE, Crispino, JD, Poncz, M, White, JG, Orkin, SH, Maris, JM and Weiss, MJ (2000) Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat. Genet. 24:266-70

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.

Links

PubMed Online version:10.1038/73480

Keywords

Adult; Amino Acid Sequence; Amino Acid Substitution; Anemia, Dyserythropoietic, Congenital/genetics; Child; Consensus Sequence; Cryptorchidism/genetics; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Erythroid-Specific DNA-Binding Factors; Female; GATA1 Transcription Factor; Hematopoiesis/genetics; Humans; Infant, Newborn; Male; Models, Molecular; Molecular Sequence Data; Pedigree; Point Mutation; Protein Structure, Tertiary; Recombinant Fusion Proteins/genetics; Thrombocytopenia/congenital; Thrombocytopenia/genetics; Transcription Factors/chemistry; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/physiology; X Chromosome/genetics; Zinc Fingers/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GATA1

involved_in

GO:0030220: platelet formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA1

involved_in

GO:0030219: megakaryocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GATA1

involved_in

GO:0008584: male gonad development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA1

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA1

involved_in

GO:0048821: erythrocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GATA1

involved_in

GO:0030218: erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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