Reference : A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytopl...
Scientific journals : Article
Human health sciences : Hematology
http://hdl.handle.net/10993/13532
A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the αIIbβ3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia
English
Ghevaert, Cedric [University of Cambridge, United Kingdom]
Salsmann, Alexandre mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Watkins, Nicholas A. [University of Cambridge, United Kingdom]
Schaffner-Reckinger, Elisabeth mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Rankin, Angela [University of Cambridge, United Kingdom]
Garner, Stephen F. [University of Cambridge, United Kingdom]
Stephens, Jonathan [University of Cambridge, United Kingdom]
Smith, Graham A. [National Health Service Blood and Transplant, Cambridge, United Kingdom]
Debili, Najet [Inserm U790, Institut Gustave Roussy, Villejuif, France]
Vainchenker, William [Inserm U790, Institut Gustave Roussy, Villejuif, France]
de Groot, Philip G. [Utrecht Medical Centre, The Netherlands]
Huntington, James A. [University of Cambridge, United Kingdom]
Laffan, Mike [Department of Haematology, Imperial College London, United Kingdom]
Kieffer, Nelly [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Ouwehand, Willem H. [University of Cambridge, United Kingdom]
2008
Blood
American Society of Hematology
111
7
3407-3414
Yes (verified by ORBilu)
0006-4971
1528-0020
Washington
DC
[en] 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 beta3 integrin and a P53L mutation in glycoprotein (GP) Ibalpha. We show that GPIbalpha-L53 is phenotypically silent, being also present in 3 unaffected pedigree members and in 7 of 1639 healthy controls. The beta3-H723 causes constitutive, albeit partial, activation of the alphaIIbbeta3 complex by disruption of the highly conserved cytoplasmic salt bridge with arginine 995 in the alphaIIb integrin as evidenced by increased PAC-1 but not fibrinogen binding to the patients' resting platelets. This was confirmed in CHO alphaIIbbeta3-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, alphaIIbbeta3-H723, but not wild-type alphaIIbbeta3, 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 alphaIIbbeta3-H723 receptor causes abnormal proplatelet formation, leading to incorrect sizing of platelets and the thrombocytopenia observed in the pedigree.
http://hdl.handle.net/10993/13532
10.1182/blood-2007-09-112615

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