New αIIbß3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains.
Platelets
; 33(4): 551-561, 2022 May 19.
Article
in En
| MEDLINE
| ID: mdl-34275420
ABSTRACT
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin αIIbß3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets αIIbß3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on αIIbß3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. αIIbp.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired αIIbß3 expression. The αIIbp.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The ß3p.Gly540Asp substitution allowed αIIbß3 expression in HEK-293 cells but induced its constitutive activation likely by impairing αIIb and ß3 legs interaction. The substitution alters the ß3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3c.1752 + 2 T > C and NM_000212.2c.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 ß3 I-EGF domains might induce constitutive activation of αIIbß3 without altering the global domain structure.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thrombasthenia
/
Platelet Glycoprotein GPIIb-IIIa Complex
/
Integrin alpha2
/
Integrin beta3
Type of study:
Prognostic_studies
Limits:
Humans
Country/Region as subject:
Asia
Language:
En
Journal:
Platelets
Journal subject:
HEMATOLOGIA
Year:
2022
Document type:
Article
Affiliation country:
Turquía