New alpha IIb beta 3 variants in 28 Turkish Glanzmann patients; Structural hypothesis for complex activation by residues variations in I-EGF domains

Creative Commons License

Koker M. Y., Sarper N., Albayrak C., Zulfikar B., Zengin E., Saraymen B., ...More

PLATELETS, vol.33, no.4, pp.551-561, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 33 Issue: 4
  • Publication Date: 2022
  • Doi Number: 10.1080/09537104.2021.1947481
  • Journal Name: PLATELETS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.551-561
  • Keywords: Hemostasis, Platelet, Glanzmann Thrombasthenia, Integrin alpha-IIb beta-3, Genetic variation, Molecular dynamics, Structural allostery, DISULFIDE BOND DISRUPTION, MOLECULAR-GENETIC-BASIS, CYSTEINE-RICH REPEAT, GLYCOPROTEIN IIIA, THROMBASTHENIA, INTEGRIN, MUTATION, IDENTIFICATION, EXPRESSION, ITGA2B
  • Erciyes University Affiliated: Yes


Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin alpha IIb beta 3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets alpha IIb beta 3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on alpha IIb beta 3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. alpha IIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired alpha IIb beta 3 expression. The alpha IIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The beta 3:p.Gly540Asp substitution allowed alpha IIb beta 3 expression in HEK-293 cells but induced its constitutive activation likely by impairing alpha IIb and beta 3 legs interaction. The substitution alters the beta 3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the beta 3 I-EGF domains might induce constitutive activation of alpha IIb beta 3 without altering the global domain structure.