A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin alpha IIb beta 3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction

作者:Miyashita Naohiro; Onozawa Masahiro*; Hayasaka Koji; Yamada Takahiro; Migita Ohsuke; Hata Kenichiro; Okada Kohei; Goto Hideki; Nakagawa Masao; Hashimoto Daigo; Kahata Kaoru; Kondo Takeshi; Kunishima Shinji; Teshima Takanori
来源:Annals of Hematology, 2018, 97(4): 629-640.
DOI:10.1007/s00277-017-3214-4

摘要

We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin alpha IIb beta 3 was partially activated in a resting status, but platelet expression of alpha IIb beta 3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in alpha IIb/beta 3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of alpha IIb beta 3 were observed in alpha IIb/beta 3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of alpha IIb beta 3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of alpha IIb beta 3 would contribute to aggregation dysfunction. We reviewed the literature of congenital macrothrombocytopenia associated with heterozygous ITGA2B or ITGB3 mutations. Reported mutations were highly clustered at the membrane proximal region of alpha IIb beta 3, which affected the critical interaction between alpha IIb R995 and beta 3 D723, resulting in a constitutionally active form of the alpha IIb beta 3 complex. Macrothrombocytopenia caused by a heterozygous activating mutation of ITGA2B or ITGB3 at the membrane proximal region forms a distinct entity of rare congenital thrombocytopenia.

  • 出版日期2018-4

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