title: Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia.
abstract: 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.
authors.affiliation: Department of Clinical Biochemistry and Molecular Pathology, the University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Balogh
authors.forename: G
authors.initials: G
authors.lastname: Szôke
authors.forename: L
authors.initials: L
authors.lastname: Kárpáti
authors.forename: U
authors.initials: U
authors.lastname: Wartiovaara
authors.forename: E
authors.initials: E
authors.lastname: Katona
authors.forename: I
authors.initials: I
authors.lastname: Komáromi
authors.forename: G
authors.initials: G
authors.lastname: Haramura
authors.forename: G
authors.initials: G
authors.lastname: Pfliegler
authors.forename: H
authors.initials: H
authors.lastname: Mikkola
authors.forename: L
authors.initials: L
authors.lastname: Muszbek
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007930:Leucine; D008297:Male; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011994:Recombinant Proteins; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D019851:Thrombophilia / Q000453:epidemiology* / Q000235:genetics*; D011503:Transglutaminases / Q000378:metabolism; D014633:Valine
chemical_list: D011994:Recombinant Proteins; D005176:Factor XIII; D011503:Transglutaminases; D013917:Thrombin; D007930:Leucine; D014633:Valine