title: Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation.
abstract: 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 beta-actin messenger RNA, showed extremely low transcription of the GATA1 target genes GPIbbeta and GPIX but also a significantly lower expression of the nondirectly GATA1-regulated Gsalpha 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 (GPIbalpha, GPIbbeta, 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.
authors: Center for Molecular and Vascular Biology, Center for Human Genetics, Department of Pathology, University of Leuven, Belgium.
authors: K
authors: K
authors: Freson
authors: K
authors: K
authors: Devriendt
authors: G
authors: G
authors: Matthijs
authors: A
authors: A
authors: Van Hoof
authors: R
authors: R
authors: De Vos
authors: C
authors: C
authors: Thys
authors: K
authors: K
authors: Minner
authors: M F
authors: MF
authors: Hoylaerts
authors: J
authors: J
authors: Vermylen
authors: C
authors: C
authors: Van Geet
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology*; D002352:Carrier Proteins / Q000187:drug effects; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000494:pharmacology; D004912:Erythrocytes / Q000473:pathology; D050981:Erythroid-Specific DNA-Binding Factors; D005192:Family Health; D005260:Female; D050982:GATA1 Transcription Factor; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000187:drug effects; D010375:Pedigree; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D013921:Thrombocytopenia / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology; D014960:X Chromosome; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D010980:Platelet Membrane Glycoproteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human