SEARCH:   Advanced

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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 20, 2007 Accepted November 28, 2007 A non-synonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the IIb3 integrin and co-segregates dominantly with abnormal proplatelet formation and macrothrombocytopenia Cedric Ghevaert*, Alexandre Salsmann, Nicholas A Watkins, Elisabeth Schaffner-Reckinger, Angela Rankin, Stephen F Garner, Jonathan Stephens, Graham A Smith, Najet Debili, William Vainchenker, Philip G de Groot, James A Huntington, Mike Laffan, Nelly Kieffer, and Willem H. Ouwehand Department of Haematology, University of Cambridge, Cambridge, United Kingdom Laboratoir de Biologie et Physiologie Integree (CNRS/GDRE-ITI), University of Luxembourg, Luxembourg, Luxembourg National Health Service Blood and Transplant, Cambridge, United Kingdom INSERM U790, Institut Gustave Roussy, Villejuif, France Department of Haematology, Utrecht Medical Centre, Utrecht, Netherlands Department of Haematology, Imperial College London, London, United Kingdom * Corresponding author; email: cg348{at}cam.ac.uk. We report a 3 generations pedigree with 5 individuals affected with a dominantly inherited macrothrombocytopenia. All 5 carry two non-synonymous mutations resulting in an aspartate723histidine (D723H) substitution in the 3 integrin and a proline53leucine (P53L) substitution in GPIb. We show that GPIb-L53 is phenotypically silent being also present in 3 unaffected pedigree members and in 7 of 1639 healthy controls. The 3-H723 causes constitutive, albeit partial, activation of the IIb3 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 IIb3-H723 transfectants which also exhibited increased PAC-1 binding, increased adhesion to vWF in static conditions and to fibrinogen under shear stress. Crucially we show that in the presence of fibrinogen, IIb3-H723, but not wild-type IIb3 generates a signal that leads to the formation of proplatelet-like protrusions in transfected CHO cells. Abnormal proplatelet formation was confirmed in the propositus' CD34+ stem cell-derived megakaryocytes. We conclude that the constitutive activation of the IIb3-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: C. Dunois-Larde, C. Capron, S. Fichelson, T. Bauer, E. Cramer-Borde, and D. Baruch Exposure of human megakaryocytes to high shear rates accelerates platelet production Blood, August 27, 2009; 114(9): 1875 - 1883. [Abstract] [Full Text] [PDF] 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]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020