Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. αIIbβ3 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 αIIbβ3 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 αIIbβ3 in 293T cells was higher for αIIb-W995 than for β3-H723 but was weaker than for β3-N562. FAK was spontaneously phosphorylated in αIIb-W995/β3-transfected 293T cells.
These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation. αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions.
The increased size and decreased number of proplatelet tips in αIIb-W995/β3-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.
2011-05-20
Eng.
Blood
Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Japan. kunishis [at] nnh.hosp.go.jp
Blood. 2011 May;117(20):5479-84
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