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Blood, 1 February 2004, Vol. 103, No. 3, pp. 948-954. Prepublished online as a Blood First Edition Paper on October 2, 2003; DOI 10.1182/blood-2003-07-2299. This Article Full Text (PDF) All Versions of this Article: 2003-07-2299v1 103/3/948    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sun, L. Articles by Rao, A K. Search for Related Content PubMed PubMed Citation Articles by Sun, L. Articles by Rao, A K. Social Bookmarking                   What's this? Submitted July 9, 2003 Accepted September 20, 2003 Association of CBFA2 mutation with decreased platelet PKC- and impaired receptor-mediated activation of GPIIb-IIIa and pleckstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation Liansheng Sun, Guangfen Mao, and A Koneti Rao* Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA; Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA * Corresponding author; email: koneti{at}temple.edu. The mechanisms by which agonists activate GPIIb-IIIa function remain unclear. We have reported (Gabbeta, et al, Blood, 87:1368, 1996) a patient with thrombocytopenia, and impaired receptor-mediated aggregation, phosphorylation of pleckstrin (a protein kinase C substrate), and activation of GPIIb-IIIa complex. Abnormalities in hematopoietic transcription factors have been associated with thrombocytopenia and platelet dysfunction. To define the molecular mechanisms, we amplified from patient platelet RNA exons 3-6 of CBFA2 cDNA, which encompasses the DNA-binding Runt domain; a 13 nucleotide deletion was found (796 nt to 808 nt). The genomic DNA revealed a heterozygous mutation (G to T) in intron 3 at the splice acceptor site for exon 4, leading to a frameshift with premature termination in the Runt domain. On immunoblotting, platelet CBFA2, PKC-, albumin, and IgG were decreased, but pleckstrin, PKC , I, II, , , and , and fibrinogen were normal. Conclusions: a) CBFA2 mutation is associated with not only thrombocytopenia, but also impaired platelet protein phosphorylation and GPIIb-IIIa activation. b) proteins regulated by CBFA2 are required for inside-out signal transduction-dependent activation of GPIIb-IIIa. c) we document the first deficiency of a human PKC isozyme (PKC-), suggesting a major role of this isozyme in platelet production and function. 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