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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.
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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.
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