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: 10.45). 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, Sep 28, 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; 165(2). DOI:10.1111/bjh.12751 · 4.71 Impact Factor
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    • "Particularly highlighted were three non-conserved loop region structures (residues 71–85, 114–125 and 148–164) of human αIIb while K118 was said to form a salt bridge with E171 in the specificity-determining loop (SDL) of β3 (residues 159–188) that contains P163. The structural importance of these residues is highlighted by the large number of missense mutations in the β-propeller region of αIIb detected in patients with classic type I GT [2], [3], [27]. Crystallography also predicted that αIIb residues L116, K124 and R153 were close to one or more residues of the β3 SDL region. "
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    ABSTRACT: Mutations in ITGA2B and ITGB3 cause Glanzmann thrombasthenia, an inherited bleeding disorder in which platelets fail to aggregate when stimulated. Whereas an absence of expression or qualitative defects of αIIbβ3 mainly affect platelets and megakaryocytes, αvβ3 has a widespread tissue distribution. Little is known of how amino acid substitutions of β3 comparatively affect the expression and structure of both integrins. We now report computer modelling including molecular dynamics simulations of extracellular head domains of αIIbβ3 and αvβ3 to determine the role of a novel β3 Pro189Ser (P163S in the mature protein) substitution that abrogates αIIbβ3 expression in platelets while allowing synthesis of αvβ3. Transfection of wild-type and mutated integrins in CHO cells confirmed that only αvβ3 surface expression was maintained. Modeling initially confirmed that replacement of αIIb by αv in the dimer results in a significant decrease in surface contacts at the subunit interface. For αIIbβ3, the presence of β3S163 specifically displaces an α-helix starting at position 259 and interacting with β3R261 while there is a moderate 11% increase in intra-subunit H-bonds and a very weak decrease in the global H-bond network. In contrast, for αvβ3, S163 has different effects with β3R261 coming deeper into the propeller with a 43% increase in intra-subunit H-bonds but with little effect on the global H-bond network. Compared to the WT integrins, the P163S mutation induces a small increase in the inter-subunit fluctuations for αIIbβ3 but a more rigid structure for αvβ3. Overall, this mutation stabilizes αvβ3 despite preventing αIIbβ3 expression.
    PLoS ONE 11/2013; 8(11):e78683. DOI:10.1371/journal.pone.0078683 · 3.23 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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