Glanzmann thrombasthenia: A review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France. alan.nurden@cnrshl.u-bordeaux2
Blood (Impact Factor: 10.43). 09/2011; 118(23):5996-6005. DOI: 10.1182/blood-2011-07-365635
Source: PubMed

ABSTRACT Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetype-inherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbβ3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for β3 has a wide tissue distribution when present as αvβ3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of β3-deficiency or nonfunction are being increasingly described.

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Available from: Xavier Pillois, Jul 30, 2015
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    • "In turn, this knowledge has aided the development of the GPIIbIIIa blocking drugs that are widely used in the prevention of thrombosis during percutaneous coronary interventions (Bledzka et al, 2013). The mutations that give rise to GT are distributed throughout the ITGA2B and ITGB3 genes encoding the aIIb and b3 integrins, respectively (Nurden et al, 2011; Glanzmann Thrombasthenia Database; http://sinaicentral Consanguinity contributes to a higher prevalence of the disorder and its association with specific mutations in certain ethnic groups (e.g. "
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    ABSTRACT: Inherited platelet function disorders (PFDs), associated with normal or reduced platelet counts, account for a significant proportion of bleeding diatheses. Identification of the underlying genetic defects is difficult in the majority of cases due to the variable clinical expression of the bleeding symptoms and the redundancy of platelet receptor and signalling pathways, which add to the complexity of diagnosis. The gold standard method for phenotyping platelets, light transmission aggregometry (LTA), has allowed classification of functional defects in the majority of patients referred for investigation of suspected PFDs, while DNA-based analysis has primarily played a confirmatory role and been restricted mainly to analysis of candidate genes. Recent advances in next generation sequencing have facilitated the identification of gene defects in patients with PFDs where the underlying genetic defect was previously unknown, especially when combined with genome-wide linkage analysis. These studies have provided new insights into the mechanisms controlling platelet formation and function, and it is likely that, as understanding of the relationships between platelet phenotype and genotype increases and pipelines for the interpretation of genetic variations identified in patients are developed, DNA-based analysis will play an increasingly important role in the first-line investigation of patients with PFDs.
    British Journal of Haematology 01/2014; DOI:10.1111/bjh.12751 · 4.96 Impact Factor
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    • "Integrin aIIbb3 plays essential roles in thrombosis and hemostasis as a platelet receptor for fibrinogen and von Willebrand factor, but its role for normal platelet production and morphology is still controversial. Glanzmann thrombasthenia (GT) is a congenital bleeding disorder due to qualitative or quantitative defects of aIIbb3, and platelet counts and morphology in GT are usually normal (Tomiyama 2000; Nurden et al. 2011a). Slight but not statistically significant decrease of platelet number with normal morphology was reported in b3-knockout mice (Hodivala-Dilke et al. 1999), whereas abnormalities in platelet counts and morphology have not been reported in aIIb-knockout mice or aIIbb3-deficient dogs (Lipscomb et al. 2000; Tronik-Le Roux et al. 2000). "
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    ABSTRACT: Integrin αIIbβ3 is indispensable for normal hemostasis, but its role for thrombopoiesis is still controversial. Recently, αIIb and β3 mutations have been identified in patients with congenital macrothrombocytopenia. We analyzed three unrelated Japanese families with congenital macrothrombocytopenia. Expression and activation state of αIIbβ3 in platelets was examined by flow cytometry and immunoblotting. Sequence of whole coding region and exon-intron boundaries of ITGA2B and ITGB3 genes was performed. The effects of mutations on αIIbβ3 activation state and phosphorylation of FAK were analyzed in transfected cells. We newly identified three mutations: two mutations in highly conserved Gly-Phe-Phe-Lys-Arg sequence in juxtamembrane region of αIIb, p.Gly991Cys and p.Phe993del, and one donor site mutation of intron 13 of ITGB3 leading to 40 amino acids deletion, p.(Asp621_Glu660del), in the membrane proximal β-tail domain of β3. One patient, who showed Glanzmann thrombasthenia-like marked reduction in surface αIIbβ3 expression (3-11% of normal control), was a compound heterozygote with ITGA2B p.Gly991Cys and a novel nonsense mutation, ITGA2B p.Arg422*. All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells. These results suggest that gain-of-function mutations around membrane region of αIIbβ3 lead to abnormal platelet number and morphology with impaired surface αIIbβ3 expression.
    07/2013; 1(2):77-86. DOI:10.1002/mgg3.9
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    ABSTRACT: Mutation screening in Glanzmann thrombasthenia (GT) is now advanced. Despite the large number of genetic defects reported in the ITGA2B gene, few affect the structure of the N-terminal domain of the αIIb subunit. We now report a Catalan family where type I GT is given by compound heterozygosity within ITGA2B with a Gly13Val substitution in αIIb associated with a 13 bp deletion involving the splice site of exon 15. Molecular modelling confirmed that the Gly13Val mutation interfered with the structure of the αIIb β-propeller and confirms that a fold-back of the N-terminus to interact with residues deep within the propeller is necessary for the normal intracellular processing of the maturing αIIbβ3 integrin.
    Platelets 03/2012; DOI:10.3109/09537104.2012.665278 · 2.63 Impact Factor
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