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In silico analysis of structural modifications in and around the integrin ?IIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.

ABSTRACT: BACKGROUND:Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the ?IIb?3 integrin in platelet aggregation. Stable bent ?IIb?3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The ?IIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the ?IIb genu define GT phenotype. METHODS:Sanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT-causing missense mutations extending from the lower part of the ?-propeller, and through the thigh and upper calf-1 domains. RESULTS:A homozygous c.1772A>C transversion in exon 18 of ITGA2B coding for a p.Asp591Ala substitution in an interconnecting loop of the lower thigh domain of ?IIb in a patient with platelets lacking ?IIb?3 led us to extend our in silico modeling to all 16 published disease-causing missense variants potentially affecting the ?IIb genu. Modifications of structuring H-bonding were the major cause in the thigh domain although one mutation gave mRNA decay. In contrast, short-range changes induced in calf-1 appeared minor suggesting long-range effects. All result in severe to total loss of ?IIb?3 in platelets. The absence of mutations within a key Ca2+-binding loop in the genu led us to scan public databases; three potential single allele variants giving major structural changes were identiffied suggesting that this key region is not protected from genetic variation. CONCLUSIONS:It appears that the ?IIb genu is the object of stringent quality control to prevent platelets from circulating with activated and extended integrin.

SUBMITTER: Pillois X

PROVIDER: S-EPMC5902390 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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In silico analysis of structural modifications in and around the integrin αIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.

Pillois Xavier X Peters Pierre P Segers Karin K Nurden Alan T AT

Molecular genetics & genomic medicine 20180131 2

<h4>Background</h4>Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the αIIbβ3 integrin in platelet aggregation. Stable bent αIIbβ3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The αIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the αIIb genu define GT phenotype.<h4>Methods</h4>Sanger sequencing of ...[more]

PMID: 29385657

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Project description:Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.

Dataset Information

In silico analysis of structural modifications in and around the integrin ?IIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.

Publications

In silico analysis of structural modifications in and around the integrin αIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.

Similar Datasets

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