| Title: | A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction |
| Authors: | Miyashita, Naohiro Browse this author |
| Onozawa, Masahiro Browse this author →KAKEN DB |
| Hayasaka, Koji Browse this author |
| Yamada, Takahiro Browse this author →KAKEN DB |
| Migita, Ohsuke Browse this author |
| Hata, Kenichiro Browse this author |
| Okada, Kohei Browse this author |
| Goto, Hideki Browse this author |
| Nakagawa, Masao Browse this author |
| Hashimoto, Daigo Browse this author →KAKEN DB |
| Kahata, Kaoru Browse this author |
| Kondo, Takeshi Browse this author →KAKEN DB |
| Kunishima, Shinji Browse this author |
| Teshima, Takanori Browse this author →KAKEN DB |
| Keywords: | Congenital macrothrombocytopenia |
| FAK phosphorylation |
| ITGB3 |
| Integrin αIIbβ3 |
| Platelet |
| Issue Date: | Apr-2018 |
| Publisher: | Springer |
| Journal Title: | Annals of hematology |
| Volume: | 97 |
| Issue: | 4 |
| Start Page: | 629 |
| End Page: | 640 |
| Publisher DOI: | 10.1007/s00277-017-3214-4 |
| Abstract: | 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 αIIbβ3 was partially activated in a resting status, but platelet expression of αIIbβ3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/β3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of αIIbβ3 were observed in αIIb/β3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of αIIbβ3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of αIIbβ3 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 αIIbβ3, which affected the critical interaction between αIIb R995 and β3 D723, resulting in a constitutionally active form of the αIIbβ3 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. |
| Rights: | The final publication is available at link.springer.com |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/73417 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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