Molecular and Genetic Mechanisms of Factor XIII A Subunit Deficiency

2000 ◽  
Vol Volume 26 (Number 01) ◽  
pp. 005-010 ◽  
Author(s):  
Akitada Ichinose ◽  
Masayoshi Souri ◽  
Tomonori Izumi ◽  
Nobumasa Takahashi
Keyword(s):  
Factor Xiii ◽  
Genetic Mechanisms ◽  
A Subunit

scholarly journals Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5111-5117 ◽  
Author(s):  
Aida Inbal ◽  
Johannes Oldenburg ◽  
Manuel Carcao ◽  
Anders Rosholm ◽  
Ramin Tehranchi ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Autosomal Recessive Disorder ◽  
Allergic Reactions ◽  
Open Label ◽  
Impaired Wound Healing ◽  
Bleeding Rate ◽  
Life Threatening ◽  
A Subunit ◽  
Bleeding Episodes ◽  
Congenital Factor

Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive disorder, with most patients having an A-subunit (FXIII-A) deficiency. Patients experience life-threatening bleeds, impaired wound healing, and spontaneous abortions. In many countries, only plasma or cryoprecipitate treatments are available, but these carry a risk for allergic reactions and infection with blood-borne pathogens. The present study was a multinational, open-label, single-arm, phase 3 prophylaxis trial evaluating the efficacy and safety of a novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency. Forty-one patients ≥ 6 years of age (mean, 26.4; range, 7-60) with congenital FXIII-A subunit deficiency were enrolled. Throughout the rFXIII prophylaxis, only 5 bleeding episodes (all trauma induced) in 4 patients were treated with FXIII-containing products. The crude mean bleeding rate was significantly lower than the historic bleeding rate (0.138 vs 2.91 bleeds/patient/year, respectively) for on-demand treatment. Transient, non-neutralizing, low-titer anti-rFXIII Abs developed in 4 patients, none of whom experienced allergic reactions, any bleeds requiring treatment, or changes in FXIII pharmacokinetics during the trial or follow-up. These non-neutralizing Abs declined below detection limits in all 4 patients despite further exposure to rFXIII or other FXIII-containing products. We conclude that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. This study is registered at http://www..clinicaltrials.gov as number NCT00713648.

Immunocytochemical detection of factor XIII a—subunit in acute leukemia

1992 ◽  
Vol 16 (8) ◽  
pp. 829-836 ◽  
Author(s):  
Rosangela Invernizzi ◽  
Pasqualina De Fazio ◽  
Angela Maria Iannone ◽  
Luisa M. Zambelli ◽  
Maria Pia Rastaldi ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Factor Xiii ◽  
Immunocytochemical Detection ◽  
A Subunit

The gene for coagulation factor XIII a subunit (F13A) is distal to HLA on chromosome 6

1984 ◽  
Vol 67 (4) ◽  
pp. 406-408 ◽  
Author(s):  
P. G. Board ◽  
M. Reid ◽  
S. Serjeantson
Keyword(s):  
Factor Xiii ◽  
Coagulation Factor ◽  
Chromosome 6 ◽  
Coagulation Factor Xiii ◽  
A Subunit

Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families

2004 ◽  
Vol 2 (10) ◽  
pp. 1790-1797 ◽  
Author(s):  
A. Vysokovsky ◽  
R. Saxena ◽  
M. Landau ◽  
A. Zivelin ◽  
R. Eskaraev ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Subunit Gene ◽  
Novel Mutations ◽  
Factor Xiii Deficiency ◽  
Hereditary Factor ◽  
A Subunit

Pharmacokinetic characterization of recombinant factor XIII (FXIII)-A2 across age groups in patients with FXIII A-subunit congenital deficiency

Haemophilia ◽  
2015 ◽  
Vol 21 (3) ◽  
pp. 380-385 ◽  
Author(s):  
B. Brand-Staufer ◽  
M. Carcao ◽  
B. A. Kerlin ◽  
A. Will ◽  
M. Williams ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Age Groups ◽  
Congenital Deficiency ◽  
A Subunit

scholarly journals Identification of Potential Novel Interacting Partners for Coagulation Factor XIII B (FXIII-B) Subunit, a Protein Associated with a Rare Bleeding Disorder

2019 ◽  
Vol 20 (11) ◽  
pp. 2682 ◽  
Author(s):  
Sneha Singh ◽  
Mohammad Suhail Akhter ◽  
Johannes Dodt ◽  
Peter Volkers ◽  
Andreas Reuter ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Regulatory Protein ◽  
Coagulation Factor ◽  
Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
B Subunit ◽  
Coagulation Factor Xiii ◽  
A Subunit ◽  
Complement C1q

Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known to have pleiotropic roles outside coagulation, but the FXIII-B subunit is a relatively unexplored entity, both structurally as well as functionally. Its discovered roles so far are limited to that of the carrier/regulatory protein of its partner FXIII-A subunit. In the present study, we have explored the co-presence of protein excipients in commercial FXIII plasma concentrate FibrogamminP by combination of protein purification and mass spectrometry-based verification. Complement factor H was one of the co-excipients observed in this analysis. This was followed by performing pull down assays from plasma in order to detect the putative novel interacting partners for the FXIII-B subunit. Complement system proteins, like complement C3 and complement C1q, were amongst the proteins that were pulled down. The only protein that was observed in both experimental set ups was alpha-2-macroglobulin, which might therefore be a putative interacting partner of the FXIII/FXIII-B subunit. Future functional investigations will be needed to understand the physiological significance of this association.

scholarly journals Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2479-2486 ◽  
Author(s):  
István Balogh ◽  
Gabriella Szôke ◽  
Levente Kárpáti ◽  
Ulla Wartiovaara ◽  
Éva Katona ◽  
...  
Keyword(s):  
Protective Effect ◽  
Venous Thrombosis ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Wild Type ◽  
Thrombin Cleavage ◽  
Plasma Factor ◽  
Thrombin Activation ◽  
A Subunit ◽  
The Mean

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.

scholarly journals Four novel mutations in deficiency of coagulation factor XIII: consequences to expression and structure of the A-subunit

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 141-151 ◽  
Author(s):  
H Mikkola ◽  
VC Yee ◽  
M Syrjala ◽  
R Seitz ◽  
R Egbring ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Nonsense Mutation ◽  
Factor Xiii ◽  
Three Dimensional ◽  
Factor Xiiia ◽  
Missense Mutations ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
Core Domain ◽  
A Subunit

Abstract The characterization of naturally occurring mutations is one way to approach functionally significant domains of polypeptides. About 10 mutations have been reported in factor XIII (FXIII) A-subunit deficiency, but very little is known about the effects of the mutations on the expression or the structure of this enzyme. In this study, the recent crystallization of FXIII A-subunit and determination of the three-dimensional model were used for the first time to pursue the structural consequences of mutations in the A-subunit. The molecular analysis of four families from Sweden, Germany, and Denmark revealed four previously unreported point mutations. Three of the mutations were missense mutations, Arg326-->Gln, Arg252-->Ile, and Leu498-->Pro, and one was a nonsense mutation, a deletion of thymidine in codon for Phe8 resulting in early frameshift and premature termination of the polypeptide chain. In the case of the nonsense mutation, delT Phe8, the steady-state mRNA level of FXIII A-subunit was reduced, as quantitated by reverse transcriptase-polymerase chain reaction and solid-phase minisequencing. In contrast, none of the missense mutations affected mRNA levels, indicating the possible translation of the mutant polypeptides. However, by enzyme-linked immunosorbent analysis and immunofluorescence, all the patients demonstrated a complete lack of detectable factor XIIIA antigen in their platelets. In the structural analysis, we included the mutations described in this work and the Met242-->Thr mutation reported earlier by us. Interestingly, in the three-dimensional model, all four missense mutations are localized in the evolutionarily conserved catalytic core domain. The substitutions are at least 15 A away from the catalytic cleft and do not affect any of the residues known to be directly involved in the enzymatic reaction. The structural analyses suggest that the mutations are most likely interfering with proper folding and stability of the protein, which is in agreement with the observed absence of detectable FXIIIA antigen. Arg326, Arg252, and Met242 are all buried within the molecule. The Arg326-->Gln and Arg252-->Ile mutations are substitutions of smaller, neutral amino acids for large, charged residues. They disrupt the electrostatic balance and hydrogen-bonding interactions in structurally significant areas. The Met242-->Thr mutation is located in the same region of the core domain as the Arg252-->Ile site and is expected to have a destabilizing effect due to an introduction of a smaller, polar residue in a tightly packed hydrophobic pocket. The substitution of proline for Leu498 is predicted to cause unfavorable interatomic contacts and a disruption of the alpha-helix mainchain hydrogen-bonding pattern; it is likely to form a kink in the helix next to the dimer interface and is expected to impair proper dimerization of the A-subunits. In the case of all four missense mutations studied, the knowledge achieved from the three-dimensional model of crystallized FXIII A-subunit provides essential information about the structural significance of the specific residues and aids in understanding the biologic consequences of the mutations observed at the cellular level.

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