A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction
Autor: | Ohsuke Migita, Daigo Hashimoto, Naohiro Miyashita, Hideki Goto, Kohei Okada, Masahiro Onozawa, Shinji Kunishima, Koji Hayasaka, Takeshi Kondo, Takanori Teshima, Kenichiro Hata, Masao Nakagawa, Takahiro Yamada, Kaoru Kahata |
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Rok vydání: | 2018 |
Předmět: |
Adult
Male 0301 basic medicine Heterozygote Membrane ruffling Integrin Autosomal dominant macrothrombocytopenia CHO Cells Platelet Glycoprotein GPIIb-IIIa Complex 030204 cardiovascular system & hematology medicine.disease_cause Young Adult 03 medical and health sciences chemistry.chemical_compound Cricetulus 0302 clinical medicine Japan medicine Animals Humans Thrombopoiesis Ristocetin ITGB3 Genes Dominant Family Health Mutation biology FAK phosphorylation Platelet Congenital macrothrombocytopenia Integrin beta3 Heterozygote advantage Hematology General Medicine Middle Aged Thrombocytopenia Recombinant Proteins Pedigree Cell biology Integrin αIIbβ3 HEK293 Cells 030104 developmental biology chemistry Mutagenesis Site-Directed biology.protein Female Gene Deletion |
Zdroj: | Annals of Hematology. 97:629-640 |
ISSN: | 1432-0584 0939-5555 |
Popis: | 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. |
Databáze: | OpenAIRE |
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