X-linked thrombocytopenia caused by a novel mutation of GATA-1

A family with recessive X-linked thrombocytopenia affecting 4 males in 2 ge nerations, characterized by macrothrombocytopenia, profound bleeding, and m ild dyserythropoiesis, is described. Microsatellite linkage analysis identi fied a region of the X chromosome including the GATA-1 gene, which encodes a critical transcription factor involved in erythrocyte and megakaryocyte d evelopment. By sequencing the entire coding region of GATA-1, a 2-base muta tion was detected that results in a single amino acid substitution (glycine 208 to serine) within a highly conserved portion of the N-terminal zinc fi nger domain. Restriction fragment length polymorphism confirmed that this n ovel mutation segregated with the affected males and female carrier. Althou gh not required for DNA binding, Gly208 of GATA-1 is involved in direct int eraction with Friend of GATA-1 (FOG), a cofactor required for normal megaka ryocytic and erythroid development. These results demonstrate that the GATA -1-FOG interaction is partially disrupted by the mutation and that the grea test effect involves contact with the FOG zinc finger 9. These findings hel p describe a novel mutation of GATA-1 in humans as a cause of X-linked thro mbocytopenia, and they confirm the vital role played by this transcription factor during in vivo megakaryocyte development. (C) 2001 by The American S ociety of Hematology.