ArticleThe Journal of experimental medicine2007
A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets.
Article in The Journal of experimental medicine, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 156 citations in OpenAlex.
- Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.The Journal of experimental medicine · 2014Trial
- Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.Journal of clinical immunology · 2023Article
- The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes.Frontiers in immunology · 2023Article
- When Actin is Not Actin' Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders.Journal of innate immunity · 2021Review
- Leukocyte adhesion defect: Where do we stand circa 2019?Genes & diseases · 2020Review
- Integration of Rap1 and Calcium Signaling.International journal of molecular sciences · 2020Review
- The Genetic Architecture of High Bone Mass.Frontiers in endocrinology · 2020Review
- Phagocytic Integrins: Activation and Signaling.Frontiers in immunology · 2020Review
- TC21/RRas2 regulates glycoprotein VI-FcRγ-mediated platelet activation and thrombus stability.Journal of thrombosis and haemostasis : JTH · 2018Article
- Molecular Classification of Primary Immunodeficiencies of T Lymphocytes.Advances in immunology · 2018Review
- Phenotype analysis and clinical management in a large family with a novel truncating mutation inResearch and practice in thrombosis and haemostasis · 2017Article
- Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity.The Journal of biological chemistry · 2016Article
- Article
- T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors.Frontiers in immunology · 2015Review
- Leukocyte adhesion deficiency III - when integrins activation fails.Journal of clinical immunology · 2014Review
- Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis.F1000Research · 2014Review
- Neutrophil cell surface receptors and their intracellular signal transduction pathways.International immunopharmacology · 2013Review
- Glanzmann thrombasthenia: state of the art and future directions.Seminars in thrombosis and hemostasis · 2013Review
- Friend or foe: high bone mineral density on routine bone density scanning, a review of causes and management.Rheumatology (Oxford, England) · 2013Review
- PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth.PloS one · 2013Article
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in beta(1), beta(2), and beta(3) integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired alpha(IIb)beta(3) activation by key agonists. beta(2) integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFalpha-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil beta(2) integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.