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A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction

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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)

Submitter: 小野澤 真弘

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