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Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2001, Vol. 98, No. 1, pp. 85-92 HEMATOPOIESIS Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation Kathleen Freson, Koen Devriendt, Gert Matthijs, Achiel Van Hoof, Rita De Vos, Chantal Thys, Kristien Minner, Marc F. Hoylaerts, Jos Vermylen, and Chris Van Geet From the Center for Molecular and Vascular Biology, Center for Human Genetics, Department of Pathology and Department of Pediatrics, University of Leuven, Belgium; and Division of Hematology, A.Z. St-Jan, Brugge, Belgium. A new mutation is described in the X-linked gene GATA1, resulting in macrothrombocytopenia and mild dyserythropoietic features but no marked anemia in a 4-generation family. The molecular basis for the observed phenotype is a substitution of glycine for aspartate in the strictly conserved codon 218 (D218G) of the amino-terminal zinc finger loop of the transcription factor GATA1. Zinc finger interaction studies demonstrated that this mutation results in a weak loss of affinity of GATA1 for its essential cofactor FOG1, whereas direct D218G-GATA1 binding to DNA was normal. The phenotypic effects of this mutation in the patients' platelets have been studied. Semiquantitative RNA analysis, normalized for -actin messenger RNA, showed extremely low transcription of the GATA1 target genes GPIb and GPIX but also a significantly lower expression of the nondirectly GATA1-regulated Gs gene, suggestive of incomplete megakaryocyte maturation. In contrast, GPIIIa expression was close to normal in agreement with its early appearance during megakaryocyte differentiation. Flow cytometric analysis of patient platelets confirmed the existence of a platelet population with abnormal size distribution and reduced GPIb complex levels but with normal GPIIIa expression. It also showed the presence of very immature platelets lacking almost all membrane glycoproteins studied (GPIb, GPIb, GPIIIa, GPIX, and GPV). Patients' platelets showed weak ristocetin-induced agglutination, compatible with the disturbed GPIb complex. Accordingly, electron microscopy of the patients' platelets revealed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes. In conclusion, GATA1 mutations can lead to isolated X-linked macrothrombocytopenia without anemia. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Ghevaert, A. Salsmann, N. A. Watkins, E. Schaffner-Reckinger, A. Rankin, S. F. 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