Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIbbeta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.
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Kunishima S, Kashiwagi H, Otsu M, Takayama N, Eto K, Onodera M, Miyajima Y, Takamatsu Y, Suzumiya J, Matsubara K, Tomiyama Y, Saito H
Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIbbeta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.
Blood. 2011 May 19;117(20):5479-84. doi: 10.1182/blood-2010-12-323691. Epub 2011 Mar 31.
- PubMed ID
- 21454453 [ View in PubMed]
- Abstract
Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. alphaIIbbeta3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet alphaIIbbeta3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of alphaIIbbeta3 in 293T cells was higher for alphaIIb-W995 than for beta3-H723 but was weaker than for beta3-N562. FAK was spontaneously phosphorylated in alphaIIb-W995/beta3-transfected 293T cells. These results indicate that alphaIIb-W995/beta3 has a constitutive, activated conformation but does not induce platelet activation. alphaIIb-W995/beta3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in alphaIIb-W995/beta3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias.