ArticleHaematologica2010
L718P mutation in the membrane-proximal cytoplasmic tail of beta 3 promotes abnormal alpha IIb beta 3 clustering and lipid microdomain coalescence, and associates with a thrombasthenia-like phenotype.
Article in Haematologica, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 40 citations in OpenAlex.
- ITGA2B/ITGB3-Related Macrothrombocytopenia Associated With Gain-of-Function Mutations in ITGA2B or ITGB3 Genes.Journal of cellular and molecular medicine · 2026Review
- A nonactivatingBlood vessels, thrombosis & hemostasis · 2025Article
- Twins With an Identical Novel Mutation inAnnals of laboratory medicine · 2024Article
- Genetics of inherited thrombocytopenias.Blood · 2022Review
- Glanzmann Thrombasthenia: Perspectives from Clinical Practice on Accurate Diagnosis and Optimal Treatment Strategies.Journal of blood medicine · 2021Review
- Profiling the Genetic and Molecular Characteristics of Glanzmann Thrombasthenia: Can It Guide Current and Future Therapies?Journal of blood medicine · 2021Review
- Statistical analysis of 3D localisation microscopy images for quantification of membrane protein distributions in a platelet clot model.PLoS computational biology · 2020Article
- αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum.PloS one · 2020Article
- [Special type of Glanzmann's thrombasthenia].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2018Article
- A novel variant Glanzmann thrombasthenia due to co-inheritance of a loss- and a gain-of-function mutation ofHaematologica · 2018Article
- Human endoglin as a potential new partner involved in platelet-endothelium interactions.Cellular and molecular life sciences : CMLS · 2018Article
- An intracytoplasmic β3 Leu718 deletion in a patient with a novel platelet phenotype.Blood advances · 2017Article
- Structural and thermodynamic basis of proline-induced transmembrane complex stabilization.Scientific reports · 2016Article
- Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia.Haematologica · 2016Article
- αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide.PloS one · 2014Article
- Glanzmann thrombasthenia: state of the art and future directions.Seminars in thrombosis and hemostasis · 2013Review
- Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype.Molecular genetics & genomic medicine · 2013Article
- Genetics of familial forms of thrombocytopenia.Human genetics · 2012Review
- Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer.Breast cancer research : BCR · 2011Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSupport for the role of transmembrane and membrane-proximal domains of alpha IIb beta 3 integrin in the maintenance of receptor low affinity comes from mutational studies showing that activating mutations can induce constitutive bi-directional transmembrane signaling. DESIGN AND
methodsWe report the functional characterization of a mutant alpha IIb beta 3 integrin carrying the Leu718Pro mutation in the membrane-proximal region of the beta 3 cytoplasmic domain, identified in heterozygosis in a patient with a severe bleeding phenotype and defective platelet aggregation and adhesion.
resultsTransiently transfected cells expressed similar levels of normal and mutant alpha IIb beta 3, but surface expression of mutant alpha v beta 3 was reduced due to its retention in intracellular compartments. Cells stably expressing mutant alpha IIb beta 3 showed constitutive binding to soluble multivalent ligands as well as spontaneous fibrinogen-dependent aggregation, but their response to DTT was markedly reduced. Fibrinogen-adherent cells exhibited a peculiar spreading phenotype with long protrusions. Immunofluorescence analysis revealed the formation of alpha IIb beta 3 clusters underneath the entire cell body and the presence of atypical high-density patches of clustered alpha IIb beta 3 containing encircled areas devoid of integrin that showed decreased affinity for the fluorescent lipid analog DiIC(16) and were disrupted in cholesterol-depleted cells.
conclusionsThese findings are consistent with an important role of the membrane-proximal region of beta 3 in modulating alpha IIb beta 3 clustering and lateral redistribution of membrane lipids. Since the beta 3 mutant was associated with a thrombasthenic phenotype in a patient carrying one normal beta 3 allele, these results support a dominant role of clustering in regulating integrin alpha IIb beta 3 functions in vivo.
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