ArticleBlood2016
Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- RAP1-RHO small GTPase cross-talk mediates integrindependent and -independent platelet procoagulant response.Haematologica · 2026Article
- A novel G13-RAPGEF2-RAP1 signaling pathway critical for platelet adhesion and aggregation.Blood · 2026Article
- Roles of G proteins and their GTPase-activating proteins in platelets.Bioscience reports · 2024Review
- Structure, signal transduction, activation, and inhibition of integrin αIIbβ3.Thrombosis journal · 2023Review
- When Actin is Not Actin' Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders.Journal of innate immunity · 2021Review
- Severe bleeding and absent ADP-induced platelet aggregation associated with inherited combined CalDAG-GEFI and P2YHaematologica · 2020Article
- Subcellular localization of Rap1 GTPase activator CalDAG-GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides.Journal of thrombosis and haemostasis : JTH · 2020Article
- RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology.International journal of molecular sciences · 2020Review
- Impaired hemostatic activity of healthy transfused platelets in inherited and acquired platelet disorders: Mechanisms and implications.Science translational medicine · 2019Article
- Hereditary platelet function disorder fromHaematologica · 2019Article
- Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting.Journal of hematology & oncology · 2019Review
- RAP GTPases and platelet integrin signaling.Platelets · 2019Review
- Article
- [The clinical characteristics and molecular pathogenesis of a variant Glanzmann's thrombasthenia-like pedigree].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2018Article
- Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.Platelets · 2018Article
- Negative regulators of platelet activation and adhesion.Journal of thrombosis and haemostasis : JTH · 2018Review
- Platelets at the Vascular Interface.Research and practice in thrombosis and haemostasis · 2018Article
- Marked bleeding diathesis in patients with platelet dysfunction due to a novel mutation in RASGRP2, encoding CalDAG-GEFI (p.Gly305Asp).Platelets · 2018Article
- Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders.Haematologica · 2018Article
- Expanded repertoire ofBlood · 2017Article
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency. Although talin and kindlin-3 were normally detected, CalDAG-GEFI was undetectable in her platelets by western blotting. Genetic analysis revealed compound heterozygous CalDAG-GEFI mutations, Lys309X and Leu360del, which were responsible for CalDAG-GEFI deficiency. The functional analysis demonstrated impaired αIIbβ3 activation by various agonists except for phorbol myristate acetate, normal calcium mobilization, and impaired Rap1 activation, which were consistent with the phenotype of CalDAG-GEFI-deficient mice. Despite substantial αIIbβ3 activation at high agonist concentrations, she had severe bleeding tendency. Further functional analysis demonstrated markedly delayed αIIbβ3 activation velocity and decreased shear-induced thrombus formation. Contrary to CalDAG-GEFI-deficient mice, which showed integrin-dependent neutrophil functional abnormality, neutrophil β2 integrin activation was not impaired in the patient. Our results demonstrate the critical role of CalDAG-GEFI in rapid αIIbβ3 activation of human platelets.
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