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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3407-3414. Prepublished online as a Blood First Edition Paper on December 7, 2007; DOI 10.1182/blood-2007-09-112615. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-09-112615v1 111/7/3407    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Ghevaert, C. Articles by Ouwehand, W. H. Search for Related Content PubMed PubMed Citation Articles by Ghevaert, C. Articles by Ouwehand, W. H. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the IIbβ3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia Cedric Ghevaert1,2, Alexandre Salsmann3, Nicholas A. Watkins1,2, Elisabeth Schaffner-Reckinger3, Angela Rankin1, Stephen F. Garner1,2, Jonathan Stephens1, Graham A. Smith2, Najet Debili4, William Vainchenker4, Philip G. de Groot5, James A. Huntington1, Mike Laffan6, Nelly Kieffer3, and Willem H. Ouwehand1,2 1 Department of Haematology, University of Cambridge, Cambridge, United Kingdom; 2 National Health Service Blood and Transplant, Cambridge, United Kingdom; 3 Laboratoire de Biologie et Physiologie Intégrée, Centre National de la Recherche Scientifique/Research Group-Integrins and Transfer of Information (CNRS/GDRE-ITI), University of Luxembourg, Grand-Duchy of Luxembourg; 4 Inserm U790, Institut Gustave Roussy, Villejuif, France; 5 Department of Haematology, Utrecht Medical Centre, Utrecht, The Netherlands; and 6 Department of Haematology, Imperial College London, London, United Kingdom We report a 3-generation pedigree with 5 individuals affected with a dominantly inherited macrothrombocytopenia. All 5 carry 2 nonsynonymous mutations resulting in a D723H mutation in the β3 integrin and a P53L mutation in glycoprotein (GP) Ib. We show that GPIb-L53 is phenotypically silent, being also present in 3 unaffected pedigree members and in 7 of 1639 healthy controls. The β3-H723 causes constitutive, albeit partial, activation of the IIbβ3 complex by disruption of the highly conserved cytoplasmic salt bridge with arginine 995 in the IIb integrin as evidenced by increased PAC-1 but not fibrinogen binding to the patients' resting platelets. This was confirmed in CHO IIbβ3-H723 transfectants, which also exhibited increased PAC-1 binding, increased adhesion to von Willebrand factor (VWF) in static conditions and to fibrinogen under shear stress. Crucially, we show that in the presence of fibrinogen, IIbβ3-H723, but not wild-type IIbβ3, generates a signal that leads to the formation of proplatelet-like protrusions in transfected CHO cells. Abnormal proplatelet formation was confirmed in the propositus's CD34+ stem cell–derived megakaryocytes. We conclude that the constitutive activation of the IIbβ3-H723 receptor causes abnormal proplatelet formation, leading to incorrect sizing of platelets and the thrombocytopenia observed in the pedigree. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Sizing up platelet defects Paul F. Bray Blood 2008 111: 3302-3303. [Full Text] [PDF] This article has been cited by other articles: A. E. Geddis The regulation of proplatelet production Haematologica, June 1, 2009; 94(6): 756 - 759. [Full Text] [PDF] K. Vanhoorelbeke, S. F. De Meyer, I. Pareyn, C. Melchior, S. Plancon, C. Margue, O. Pradier, P. Fondu, N. Kieffer, T. A. Springer, et al. The Novel S527F Mutation in the Integrin {beta}3 Chain Induces a High Affinity {alpha}IIb{beta}3 Receptor by Hindering Adoption of the Bent Conformation J. Biol. Chem., May 29, 2009; 284(22): 14914 - 14920. [Abstract] [Full Text] [PDF] C. Kim, T.-L. Lau, T. S. Ulmer, and M. H. Ginsberg Interactions of platelet integrin {alpha}IIb and {beta}3 transmembrane domains in mammalian cell membranes and their role in integrin activation Blood, May 7, 2009; 113(19): 4747 - 4753. [Abstract] [Full Text] [PDF] N. Soranzo, A. Rendon, C. Gieger, C. I. Jones, N. A. Watkins, S. Menzel, A. Doring, J. Stephens, H. Prokisch, W. Erber, et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function Blood, April 16, 2009; 113(16): 3831 - 3837. [Abstract] [Full Text] [PDF] Y. Imai, E. J. Park, D. Peer, A. Peixoto, G. Cheng, U. H. von Andrian, C. V. Carman, and M. Shimaoka Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates {alpha}4 integrins Blood, December 15, 2008; 112(13): 5007 - 5015. [Abstract] [Full Text] [PDF]

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