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Modelling Studies to Characterize a Novel Disease-causing Variant in the GP1BA Gene Related to Bernard Soulier Syndrome

D.M Primrose1, A.I. Woods2, M.F Alberto3, J. Paiva3, M. Asencio3, M.M Casinelli3, A.N Blanco3, A. Sánchez-Luceros3,2

1Higher School of Engineering, Informatics and Agri-food Sciences, University of Morón, Morón City, Argentina, 2Laboratory of Hemostasis and Thrombosis, IMEX-CONICET-National Academy of Medicine. Buenos Aires City, Argentina, Ciudad Autonoma de Buenos Aires, Argentina, 3Departament of Hemostasis and Thrombosis, Hematological Research Institute, National Academy of Medicine, Ciudad Autonoma de Buenos Aires, Argentina

Abstract Number: PB0894

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Platelet Function Disorders, Hereditary

Background: We described a novel disease-causing variant (DCV) p.Tyr231Cys in the GP1BA gene related to recessive BSS in a patient with no bleeding symptoms and 50% CD42b-expression. Homology modelling was used to describe the effects of this DCV on protein-protein interaction.

Aims: To study effect of the GPIbα-p.Tyr231Cys on the interaction of GPIbα with VWF-A1 domain by homology modelling.

Methods: The model GPIbα-p.Tyr231Cys was made by replacing Tyr231 by Cys in wild-type-GPIbα (Swiss-PDBviewer). Docking between VWF-A1 and GPIbα-p.Tyr231Cys was obtained (PatchDock) and compared to WT-GPIbα-VWF-A1. Hydrogen-bonds and root-mean-square deviation (RMSD) between α-carbon chains were obtained (UCSF Chimera).

Results: GPIbα-Tyr231 is found in the a2-helix, nearby two disulphide-bonds: C225-C264; C227-C280. No new disulphide-bonds are predicted in GPIbα-p.Tyr231Cys. GPIbα-Tyr231 forms intramolecular hydrogen-bonds with Phe208, Trp235 and Glu228.In p.Cys231Tyr, hydrogen-bond with Phe208 is lost and a new bond is formed with Ile203. The bond with Trp235 is maintained and is still present with Glu228 but at a larger distance, consequently, weaker.
In silico-model of wild-type-GPIbα-VWF-A1 (Fig-1A) shows differences with GPIbα-p.Tyr231Cys-VWF-A1(Fig-1B). Total RMSD between models is 38.05Å (0.65Å between GPIbα portions; 15.07Å between VWF-A1 domains) (Fig-1C). The change Tyr231Cys causes a slight alteration in the conformation of GPIba (0.65Å) respecting wild-type-GPIbα. This change does not affect neighboring residues but alters the structure of GPIbα at the site that acts as a hinge, increasing the distance of the b-switch region of GPIba (flexible loop at Val243-Ser257). This modifies the interaction with VWF-A1, changing hydrogen-bonds between these molecules (Table 1).

Hypothetical model of GPIba with the A1 domain of VWF. A) A1 (cian) with wild-type GPIba (magenta); B) A1 (orange) with mutated GPIba-p.Tyr231Cys; C) overlap of both models

Wild-type-GPIba Residue on GPIba Residue on VWF-A1 domain H-bond Distance/Å
Lys253 Ala1327 3.0
3.2
Met255 Ser1325 3.0
2.9
GPIba-Tyr231Cys Gln143 Lys1371 1.7
Ile1368 3.6
Glu241 His1322 3.2
Asp251 Arg1336 3.4
Ser1338 3.2

Predicted hydrogen-bonds distance between wild-type-GPIba and the VWF-A1 domain and between GPIba-p.Tyr231Cys and the VWF-A1 domain

Conclusions: In-silico predictions show that GP1BA-p.Tyr231Cys modifies the tertiary structure of GPIba affecting the interaction with VWF-A1, explaining its negative effect that influences in both platelet count and size and in 50% expression of GPIb as observed in our patient. The change Tyr231Cys could be preventing the conformational change of the b-switch from compact to extended thus altering the VWF-GPIbα binding.

To cite this abstract in AMA style:

M Primrose D, Woods AI, F Alberto M, Paiva J, Asencio M, M Casinelli M, N Blanco A, Sánchez-Luceros A. Modelling Studies to Characterize a Novel Disease-causing Variant in the GP1BA Gene Related to Bernard Soulier Syndrome [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/modelling-studies-to-characterize-a-novel-disease-causing-variant-in-the-gp1ba-gene-related-to-bernard-soulier-syndrome/. Accessed November 29, 2023.

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