Identification of three novel pathogenic ITGA2B and one novel pathogenic ITGB3 mutations in patients with hereditary Glanzmann’s thrombasthenia living in Eastern Turkey

Karaman, Kamuran; Yürektürk, Eyüp; Geylan, Hadi; Yaşar, Akkız Şahin; Karaman, Serap; Aymelek, Huri Sema; Çetin, Mecnun; Öner, Ahmet Fayık

doi:10.1080/09537104.2020.1732331

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…F171C affects the interface involving β‐propeller and βI domains of αIIb and β3 subunits, respectively, thereby abrogating complex formation 12 . Recent studies on GT patients have also reported mutations that demonstrated the impact of β‐propeller mutations on αIIbβ3 biogenesis and ligand binding 13,14 . We had previously described three novel missense mutations, namely G128S, S287L, and G357S, within β‐propeller blades 2, 5, and 6 located at this interface.…”

Section: Introductionmentioning

confidence: 97%

“…12 Recent studies on GT patients have also reported mutations that demonstrated the impact of βpropeller mutations on αIIbβ3 biogenesis and ligand binding. 13,14 We had previously described three novel missense mutations, namely G128S, S287L, and G357S, within β-propeller blades 2, 5, and 6 located at this interface. Transfection studies revealed that mutant pro-αIIb was synthesized in each case and heterodimerized with β3 similar to wild-type αIIb.…”

Section: Introductionmentioning

confidence: 99%

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Molecular dynamics simulations corroborate recombinant expression studies carried out on three αIIb β‐propeller mutations reported in Indian Glanzmann thrombasthenia patients

Chandrasekaran,

Vishal,

Arora

et al. 2023

J of Cellular Biochemistry

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Mutations in the αIIb β‐propeller domain have long been known to disrupt heterodimerization and intracellular trafficking of αIIbβ3 complexes leading to diminished surface expression and/or function, resulting in Glanzmann thrombasthenia. Our previous study on three β‐propeller mutations, namely G128S, S287L, and G357S, showed variable defects in protein transport correlated with the patient's clinical phenotypes. Pulse‐chase experiments revealed differences in αIIbβ3 complex maturation among the three mutations. Hence, the current study aims to correlate conformational changes caused by each one of them. Evolutionary conservation analysis, stability analysis, and molecular dynamics simulations of the three mutant structures were carried out. Stability analysis revealed that, while G128S and G357S mutations destabilized the β‐propeller structure, S287L retained the stability. Wild‐type and mutant β‐propeller structures, when subjected to molecular dynamics simulations, confirmed that G128S and G357S were both destabilizing in nature when compared with the wild‐type and S287L based on several parameters studied, like RMSD, RMSF, Rg, FEL, PCA, secondary structure, and hydrogen bonds. In our previous study, we demonstrated that mutant S287L αIIbβ3 complexes were more stable than the wild‐type αIIbβ3 complexes, as evidenced in pulse‐chase experiments. These findings corroborate variable intracellular fates of mutant αIIbβ3 complexes as a result of these β‐propeller mutations.

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Section: Introductionmentioning

confidence: 97%