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Thromb Haemost 2005; 93(05): 904-909
DOI: 10.1160/TH04-12-0848
Platelets and Blood Cells
Schattauer GmbH

A novel homozygous mutation (1619delC) in GPIIb gene associated with Glanzmann thrombasthenia, the decay of GPIIb-mRNA and the synthesis of a truncated GPIIb unable to form complex with GPIIIa

Gergely Losonczy
1   Clinical Research Center, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Nurit Rosenberg
2   Amalia Biron Research Institute of Thrombosis and Hemostasis, The Chaim Sheba Medical Center, Tel-Hashomer, Israel
,
Csongor Kiss
3   Department of Pediatrics, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
János Kappelmayer
4   Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
György Vereb
5   Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Adrienne Kerényi
4   Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
István Balogh
4   Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
László Muszbek
1   Clinical Research Center, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
6   Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
› Author AffiliationsFinancial support: This study was supported by grants from the Hungarian National Research Fund (OTKA T043086, TS044796, TFO38301), from the Hungarian Academy of Sciences (MTA 11003) and from the Hungarian Ministry of Education (FKFP 0214/2001). G. V. was supported by Békéssy fellowship. I. B. was supported by Magyary fellowship.
Further Information

Publication History

Received 31 December 2004

Accepted after revision 07 February 2005

Publication Date:
11 December 2017 (online)

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Summary

The absence of agonist-induced platelet aggregation and the lack of fibrinogen receptor (GPIIb/IIIa) on the platelet surface demonstrated that the severe hemorrhagic complications of a child of Romany descent were caused by Glanzmann thrombasthenia. DNA sequencing revealed a novel homozygous deletion of a cytosine (1619delC) in the GPIIb gene causing a frameshift and predicting a novel stop codon at position 533 following 24 altered amino acids. Both parents possessed the same deletion in heterozygous form. The amount of GPIIb mRNA in the patient’s platelets was 0.06% of the amount measured in control platelets. Neither GPIIb nor its truncated form could be detected in the platelets of the patient by Western blotting, while a small amount of GPIIIa was demonstrated. Quantitative flow cytometric analysis showed an elevated number of vitronectin receptors, a component of which is GPIIIa, on the patient’s platelets. The surface expression of vitronectin receptor on thrombasthenic, but not on normal platelets was further increased by activation with thrombin receptor agonist peptide. BHK cells transfected with wild type GPIIIa and mutated GPIIb failed to express any mature GPIIb or pro-GPIIb. Immunoprecipitation with a polyclonal antibody recognizing both GPIIb and GPIIIa recovered a 60 kDa truncated form of GPIIb. This band was absent when immunoprecipitation was carried out with an antibody recognizing GPIIIa, suggesting that the truncated protein, lacking calf-1, calf-2 domains and major part of the thigh domain, is unable to form complex with GPIIIa.

Keywords

Fibrinogen receptor - Glanzmann thrombasthenia - glycoprotein IIb mutation - truncated glycoprotein IIb - vitronectin receptor
 

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