New αIIbβ3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains

Koker, Mustafa Yavuz; Sarper, Nazan; Albayrak, Canan; Zülfikar, Bulent; Zengin, Emine; Saraymen, Berkay; Albayrak, Davut; Koç, Başak; Avcilar, Huseyin; Karakükçü, Musa; Chenet, Christophe; Bianchi, F.; Brevern, Alexandre G. de; Petermann, Rachel; Jallu, Vincent

doi:10.1080/09537104.2021.1947481

Cited by 3 publications

(2 citation statements)

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“…Other large series included 28 patients from 20 families in Turkey, and selected families with IPDs suggestive of GT from Pakistan. 47,48 High levels of consanguinity led to a high percentage of homozygous mutations and the identification of ethnic-specific founder mutations.…”

Section: Genotyping and Next-generation Sequencingmentioning

confidence: 99%

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Nurden,

Nurden

2024

Semin Thromb Hemost

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Glanzmann thrombasthenia (GT) is the most common inherited platelet disorder (IPD) with mucocutaneous bleeding and a failure of platelets to aggregate when stimulated. The molecular cause is insufficient or defective αIIbβ3, an integrin encoded by the ITGA2B and ITGB3 genes. On activation αIIbβ3 undergoes conformational changes and binds fibrinogen (Fg) and other proteins to join platelets in the aggregate. The application of next-generation sequencing (NGS) to patients with IPDs has accelerated genotyping for GT; progress accompanied by improved mutation curation. The evaluation by NGS of variants in other hemostasis and vascular genes is a major step toward understanding why bleeding varies so much between patients. The recently discovered role for glycoprotein VI in thrombus formation, through its binding to fibrin and surface-bound Fg, may offer a mechanosensitive back-up for αIIbβ3, especially at sites of inflammation. The setting up of national networks for IPDs and GT is improving patient care. Hematopoietic stem cell therapy provides a long-term cure for severe cases; however, prophylaxis by monoclonal antibodies designed to accelerate fibrin formation at injured sites in the vasculature is a promising development. Gene therapy using lentil-virus vectors remains a future option with CRISPR/Cas9 technologies offering a promising alternative route.

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Section: Genotyping and Next-generation Sequencingmentioning

confidence: 99%

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Nurden,

Nurden

2024

Semin Thromb Hemost

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“…A similar analysis with a new GT variant G540D of β3 I-EGF-3 discovered in Turkish families revealed a strong impact in terms of dynamics. The GT variant showed disorder tendencies in the second part of I-EGF-3 whereas it was rigid or slightly flexible at most [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

Anies

Jallu²,

Diharce

et al. 2022

IJMS

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Integrin αIIbβ3, a glycoprotein complex expressed at the platelet surface, is involved in platelet aggregation and contributes to primary haemostasis. Several integrin αIIbβ3 polymorphisms prevent the aggregation that causes haemorrhagic syndromes, such as Glanzmann thrombasthenia (GT). Access to 3D structure allows understanding the structural effects of polymorphisms related to GT. In a previous analysis using Molecular Dynamics (MD) simulations of αIIb Calf-1 domain structure, it was observed that GT associated with single amino acid variation affects distant loops, but not the mutated position. In this study, experiments are extended to Calf-1, Thigh, and Calf-2 domains. Two loops in Calf-2 are unstructured and therefore are modelled expertly using biophysical restraints. Surprisingly, MD revealed the presence of rigid zones in these loops. Detailed analysis with structural alphabet, the Proteins Blocks (PBs), allowed observing local changes in highly flexible regions. The variant P741R located at C-terminal of Calf-1 revealed that the Calf-2 presence did not affect the results obtained with isolated Calf-1 domain. Simulations for Calf- 1+ Calf-2, and Thigh + Calf-1 variant systems are designed to comprehend the impact of five single amino acid variations in these domains. Distant conformational changes are observed, thus highlighting the potential role of allostery in the structural basis of GT.

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