RSS-Feed abonnieren
PDF herunterladen
DOI: 10.1055/s-0037-1614073
Effect of Val34Leu Polymorphism on the Activation of the Coagulation Factor XIII-A
This study was supported by grants from the Juselius Foundation, the Clinical Research Institute of HUCH, the Finnish Association of Haematology, The Finnish Medical Foundation, the Helsinki University 350 Anniversary Foundation, The Ulla Hjelt Fund, the Hungarian National Research Fund (OTKA/030406), the Hungarian Ministry of Health (321/1996) and the Hungarian Academy of Sciences. The travel grant from European Thrombosis Research Organization to Ulla Wartiovaara for working at the University of Debredcen is gratefully acknowledged.
Publikationsverlauf
Received
06. Juli 1999
Accepted after resubmission
21. April 2000
Publikationsdatum:
11. Dezember 2017 (online)
Summary
Coagulation factor XIII (FXIII) is a protransglutaminase involved in the last step of the coagulation cascade by stabilising the fibrin clot. Recently, a common variation (FXIII Val34Leu) has been associated with a decreased risk of myocardial infarction and deep venous thrombosis. Val34Leu is critically located near the thrombin activation site of FXIII-A. In this study we investigated its effects on the activation of FXIII. Both recombinant and platelet-derived FXIII Val34Leu variants were shown to be more susceptible to thrombin cleavage than the wild type FXIII. The rate of enzymatic activation of FXIII Val34Leu was found increased, however, the specific activity of fully activated wild type FXIII and the Val34Leu mutant did not differ. During the course of thrombin-induced activation of FXIII fibrin γ-chain dimerisation and α-chain polymerisation developed more rapidly with the Val34Leu mutant. The increased rate of fibrin stabilisation brought about by the Val34Leu FXIII seems to be paradoxically associated with a protective effect against pathological thrombosis.
Abbreviations: AP, activation peptide of factor XIII; FXIII, blood coagulation factor XIII; FXIII-A, factor XIII subunit A; FXIII-A’, proteolytically activated subunit A; FXIII-B, factor XIII subunit B; SDS PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis
-
References
- 1 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: Structure and function. Thromb Res 1999; 94: 271-305.
- 2 Mikkola H, Syrjälä M, Rasi V, Vahtera E, Peltonen L, Palotie A. Deficiency in the A-subunit of coagulation factor XIII: Two novel point mutations demonstrate different effects on transcript levels. Blood 1994; 84: 517-25.
- 3 Mikkola H, Yee VC, Syrjälä M, Seitz R, Egbring R, Petrini P, Ljung R, Ingerslev J, Teller DC, Peltonen L, Palotie A. Four novel mutations in deficiency of coagulation factor XIII: Consequences to expression and structure of the A-subunit. Blood 1996; 87: 141-51.
- 4 Mikkola H, Muszbek L, Laiho E, Syrjälä M, Hämäläinen E, Haramura G, Salmi T, Peltonen L, Palotie A. Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: A splicing mutation permitting correct splicing of FXIII A-subunit mRNA. Blood 1997; 89: 1279-87.
- 5 Mikkola H, Muszbek L, Haramura G, Hämäläinen E, Jalanko A, Palotie A. Molecular mechanisms of mutations in factor XIII A-subunit deficiency: in vitro expression in COS-cells demonstrates intracellular degradation of the mutant proteins. Thromb Haemost 1997; 77 (06) 1068-74.
- 6 Muszbek L, Polgar J, Boda Z. Platelet factor XIII becomes active without the release of activation peptide during platelet activation. Thromb Haemost 1993; 69 (03) 282-5.
- 7 Mikkola H. Molecular basis of coagulation factor XIII deficiency. Academic dissertation, Faculty of Medicine, University of Helsinki. Finland. 1997
- 8 Anwar R, Gallivan L, Miloszewski KJ, Markham AF. Splicing and missense mutations in the human FXIII-A gene causing FXIII deficiency: effects of these mutations on FXIII-A RNA processing and protein structure. Br J Haematol 1998; a 103 (02) 425-8.
- 9 Anwar R, Miloszewski KJ, Markham AF. New splicing mutations in the human factor XIIIA gene, each producing multiple mutant transcripts of varying abundance. Thromb Haemost 1998; b 79 (06) 1151-6.
- 10 Anwar R, Miloszewski KJ, Markham AF. Identification of a large deletion, spanning exons 4 to 11 of the human factor XIIIA gene, in a factor XIII-deficient family. Blood 1998; c 91 (01) 149-53.
- 11 Wartiovaara U, Perola M, Mikkola H, Tötterman K, Savolainen V, Penttilä A, Grant PJ, Tikkanen MJ, Vartiainen E, Karhunen PJ, Peltonen L, Palotie A. Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males. Atherosclerosis 1999; 142: 295-300.
- 12 Kohler HP, Stickland MH, Ossei-Gerning N, Carter A, Mikkola H, Grant PJ. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost 1998; 79: 8-13.
- 13 Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93 (03) 906-8.
- 14 Franco RF, Reitsma PH, Lourenco D, Maffei FH, Morelli V, Tavella MH, Araujo AG, Piccinato CE, Zago MA. Factor XIII Val34Leu is a genetic factor involved in the aetiology of venous thrombosis. Thromb Haemost 1999; 81 (05) 676-80.
- 15 Kansadalampai S, Board PG. The Val34Leu polymorphism in the A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood 1998; 92: 2766-70.
- 16 Anwar R, Gallivan L, Edmonds SD, Markham AF. Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood 1999; 93 (03) 897-905.
- 17 Kohler HP, Ariens RAS, Whitaker P, Grant PJ. A common coding polymorphism in the FXIII A-subunit gene (FXIIIVal34Leu) affects cross-linking activity. Thromb Haemost 1998; 80: 704.
- 18 Syvänen AC, Sajantila A, Lukka M. Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. Am J Hum Genet 1993; 52: 46-59.
- 19 Ihalainen J, Siitari H, Laine S, Syvänen AC, Palotie A. Towards automatic detection of point mutations: use of scintillating microplates in solid-phase minisequencing. BioTechniques 1994; 16: 938-43.
- 20 Sussman DJ, Milman G. Short-term, high-efficiency expression of transfected DNA. Mol Cell Biol 1984; 04: 1641-3.
- 21 Bohn H. Isolierung und Characterisierung des fibrinstabilisierenden Faktors aus menschlichen Thrombozyten. Thromb Diath Haemorrh 1970; 23: 455-68.
- 22 Schwartz ML, Pizzo SV, Hill RL, McKee PA. The subunit structure of human plasma and platelet factor XIII (Fibrin-stabilizing factor). J Biol Chem 1971; 246 (18) 5851-4.
- 23 Janus TJ, Lewis SD, Lorand L, Shafer JA. Promotion of thrombin-catalyzed activation of factor XIII by fibrinogen. Biochemistry 1983; 22: 6269-72.
- 24 Katona É, Haramura G, Kárpáti L, Fachet J, Muszbek L. A Simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2). Thromb Haemost 2000; 83: 268-73.
- 25 Katona É, Haramura G, Fachet J, Muszbek L. Highly sensitive, rapid one step ELISA assays for the determination of plasma and cellular factor XIII. Thromb Haemost 1999; suppl. Abstract book: 697.
- 26 Lorand L, Campbell-Wilkes LK, Cooperstein L. A filter paper assay for transamidating enzymes using radioactive amine substrates. Anal Biochem 1972; 50 (02) 623-31.
- 27 Muszbek L, Polgar J, Fesus L. Kinetic determination of blood coagulation factor XIII in plasma. Clin Chem 1985; 31 (01) 35-40.
- 28 Kárpáti L, Muszbek L. An improved photometric assay for the determination of blood coagulation factor XIII in plasma. Thromb Haemost 1999; suppl. Abstract book: 698.
- 29 Hársfalvi J, Brosstad F, Muszbek L. Platelet adhesion and plasmin generation on immobilized and FXIII crosslinked fibrin(ogen). Fibrinolysis Proteolysis 1998; 12: 48a.