X-linked thrombocytopenia caused by a novel mutation of GATA-1.
A family with recessive X-linked thrombocytopenia affecting 4 males in 2 generations, characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis, is described. Microsatellite linkage analysis identified a region of the X chromosome including the GATA-1 gene, which encodes a critical transcription factor involved in erythrocyte and megakaryocyte development. By sequencing the entire coding region of GATA-1, a 2-base mutation was detected that results in a single amino acid substitution (glycine 208 to serine) within a highly conserved portion of the N-terminal zinc finger domain. Restriction fragment length polymorphism confirmed that this novel mutation segregated with the affected males and female carrier. Although not required for DNA binding, Gly208 of GATA-1 is involved in direct interaction with Friend of GATA-1 (FOG), a cofactor required for normal megakaryocytic and erythroid development. These results demonstrate that the GATA-1-FOG interaction is partially disrupted by the mutation and that the greatest effect involves contact with the FOG zinc finger 9. These findings help describe a novel mutation of GATA-1 in humans as a cause of X-linked thrombocytopenia, and they confirm the vital role played by this transcription factor during in vivo megakaryocyte development.
Mehaffey
M G
MG
Puget Sound Blood Center and Program, Seattle, WA 98104, USA.
Newton
A L
AL
Gandhi
M J
MJ
Crossley
M
M
Drachman
J G
JG
D001853:Bone Marrow; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005192:Family Health; D005260:Female; D050982:GATA1 Transcription Factor; D008040:Genetic Linkage; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010375:Pedigree; D011485:Protein Binding / Q000235:genetics; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology / Q000235:genetics*; D013926:Thrombopoietin / Q000097:blood; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome; D016335:Zinc Fingers / Q000235:genetics
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human; D013926:Thrombopoietin