| Autor: |
Koker, M Y, Sarper, N, Albayrak, C, Zulfikar, B, Zengin, E, Saraymen, B, Albayrak, D, Koc, B, Avcilar, H, Karakükcü, M, Chenet, C, Bianchi, F, de Brevern, A G, Petermann, R, Jallu, V |
| Předmět: |
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| Zdroj: |
Platelets; 2022, Vol. 33 Issue 4, p551-561, 11p |
| Abstrakt: |
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin αIIbβ3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets αIIbβ3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on αIIbβ3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. αIIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired αIIbβ3 expression. The αIIb: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 β3:p.Gly540Asp substitution allowed αIIbβ3 expression in HEK-293 cells but induced its constitutive activation likely by impairing αIIb and β3 legs interaction. The substitution alters the β3 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 β3 I-EGF domains might induce constitutive activation of αIIbβ3 without altering the global domain structure. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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