Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia
| Autor: | Hanna K. A. Mikkola, Istvan Balogh, István Komáromi, Gizella Haramura, László Muszbek, György Pfliegler, Gabriella Szóke, Levente Kárpáti, Ulla Wartiovaara, Éva Katona |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
medicine.medical_specialty
Tissue transglutaminase Immunology Mutant 030204 cardiovascular system & hematology Thrombophilia Biochemistry 03 medical and health sciences 0302 clinical medicine Thrombin Valine Internal medicine Blood plasma medicine Allele 030304 developmental biology 0303 health sciences biology Chemistry Cell Biology Hematology medicine.disease Factor XIII Endocrinology biology.protein medicine.drug |
| Zdroj: | Blood. 96:2479-2486 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia. |
| Databáze: | OpenAIRE |
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