Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation
| العنوان: | Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation |
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| المؤلفون: | Shigenori Honda, Hirokazu Kashiwagi, Yumi Kurokawa, Yozo Nakazawa, Hisashi Kato, Yoshiaki Tomiyama, Daisuke Morita, Fumiaki Banno, Yoichiro Morikawa, Yuzuru Kanakura |
| المصدر: | Blood. 128:2729-2733 |
| بيانات النشر: | American Society of Hematology, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, Immunology, Integrin, chemistry.chemical_element, 030204 cardiovascular system & hematology, Calcium, Fibrinogen, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Platelet, Hemostatic function, Diacylglycerol kinase, biology, Chemistry, Cell Biology, Hematology, 030104 developmental biology, Endocrinology, Hemostasis, biology.protein, Signal transduction, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::f92de86d875995876ca254b134eefa4dTest https://doi.org/10.1182/blood-2016-03-704825Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi...........f92de86d875995876ca254b134eefa4d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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