scholarly journals Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency

2003 ◽  
Vol 23 (1) ◽  
pp. 98-98 ◽  
Author(s):  
Flora Peyvandi ◽  
Liliana Tagliabue ◽  
Marzia Menegatti ◽  
Mehran Karimi ◽  
Istvan Komáromi ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Factor Xiii Deficiency ◽  
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

Spontaneous regression of the inhibitor against the coagulation factor XIII A subunit in acquired factor XIII deficiency

2010 ◽  
Vol 104 (12) ◽  
pp. 1284-1285 ◽  
Author(s):  
Kentaro Okubo ◽  
Toshiro Ito ◽  
Nobuo Okumura ◽  
Masayoshi Souri ◽  
Akitada Ichinose ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Spontaneous Regression ◽  
Coagulation Factor ◽  
Factor Xiii Deficiency ◽  
Coagulation Factor Xiii ◽  
A Subunit

Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody

Haemophilia ◽  
2015 ◽  
Vol 22 (2) ◽  
pp. 268-275 ◽  
Author(s):  
K. Pénzes ◽  
C. Vezina ◽  
Z. Bereczky ◽  
É. Katona ◽  
M. Kun ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Substitution Therapy ◽  
Deficient Patient ◽  
A Subunit

Physiopathology and Regulation of Factor XIII

2001 ◽  
Vol 86 (07) ◽  
pp. 57-65 ◽  
Author(s):  
Akitada Ichinose
Keyword(s):  
Factor Xiii ◽  
Mrna Level ◽  
Factor Xiii Deficiency ◽  
Specific Expression ◽  
Nonsense Mutations ◽  
B Subunit ◽  
Cell Type Specific Expression ◽  
A Subunit ◽  
Cell Type Specific ◽  
Substrate Proteins

SummaryFactor XIII is a plasma transglutaminase. Transglutaminases are at least 8 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII in plasma is a tetramer (A2B2), and the A subunit contains the active site. Although transglutaminases are homologous, the nucleotide sequences in their 5’-flanking region differ significantly. Accordingly, transcription factors play a major role in the cell type-specific expression of each transglutaminase. A variety of missense and nonsense mutations, and deletions/insertions with or without out-of-frame shift/premature termination and splicing abnormalities have been identified in the genes for A and B subunits in factor XIII deficiency. In some cases, the mRNA level of the A or B subunit was severely reduced. Molecular and cellular bases have also been explored by expression experiments and by molecular modeling. In most cases, impaired folding and/or conformational change of the mutant A or B subunit leads to both intra- and extra-cellular instability, which is responsible for factor XIII deficiency.

Novel Deletion and Insertion Mutations Cause Splicing Defects, Leading to Severe Reduction in mRNA Levels of the A Subunit in Severe Factor XIII Deficiency

1998 ◽  
Vol 79 (03) ◽  
pp. 479-485 ◽  
Author(s):  
Tomonori Izumi ◽  
Utako Nagaoka ◽  
Tetsuo Saito ◽  
Junki Takamatsu ◽  
Hidehiko Saito ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Molecular Mechanisms ◽  
Donor Site ◽  
Pcr Analysis ◽  
Nucleotide Sequence Analysis ◽  
Mrna Levels ◽  
Factor Xiii Deficiency ◽  
Dna And Rna ◽  
Severe Reduction ◽  
A Subunit

SummaryIn order to explore molecular mechanisms for factor XIII deficiency, a patient (Nagoya I) was examined at the DNA and RNA levels. Nucleotide sequence analysis of the patient’s DNA amplified by PCR revealed that he had a 20 bp deletion at the boundary of exon I/intron A, and an insertion of T in the invariant GT dinucleotide at the splicing donor site of exon IV/intron D. The presence of these heterozygous mutations was confirmed by restriction digestion of the amplified fragments of the proband and his parents. RT-PCR analysis demonstrated that only one kind of mRNA without exon IV was detected in Nagoya I, although its level was greatly reduced to less than 5% of normal. The other defective allele of the A subunit gene containing the 20 bp deletion was not detected. Thus, both mutations impaired normal processing of mRNA for the A subunit, resulting in his severe factor XIII deficiency.

A Novel 3-Base Pair 1834–1836 AAG-Deletion (Lys570Del) Mutation In Factor XIII A Subunit Associated with Factor XIII Deficiency

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1412-1412
Author(s):  
Anamika Singh ◽  
A. Koneti Rao
Keyword(s):  
Factor Xiii ◽  
Bleeding Tendency ◽  
Compound Heterozygosity ◽  
Factor Xiii Deficiency ◽  
Catalytic Core ◽  
A Subunit ◽  
A Chain ◽  
The Impact ◽  
Fxiii Activity ◽  
Fxiii Deficiency

Abstract Abstract 1412 Factor XIII is a transglutaminase that cross-links proteins in plasma, vascular matrix, endothelial cells, platelets and monocytes, and plays a role in atherosclerosis, wound healing, and inflammation. Plasma FXIII molecule is a hetero-tetramer consisting of two catalytic A-subunits and two B-subunits that act as carrier molecules. The gene encoding FXIII A subunit comprises of 15 exons spanning 160 kb and the mature protein contains 731 amino acids. FXIII deficiency is a rare autosomal recessive disorder affecting ∼1 in 1–3 million people. It is characterized by bleeding, impaired wound repair and spontaneous abortions. We report studies from a family where two children son (13 yrs) and daughter (11 yrs) have had a lifelong bleeding tendency and spontaneous intracranial hemorrhages. Both parents were asymptomatic and there was no consanguinity. The results of routine laboratory tests, prothrombin time and activated partial thromboplastin time were normal in all subjects. The plasma FXIII activity by a commercially available chromogenic assay was 5% in the son and <3% in the daughter (normal range 57–192%). The FXIII activity in the father and mother were 198% and 74%, respectively. We have identified a novel deletion mutation, which has not been reported so far in FXIII deficiency. Leukocyte RNA was isolated from the buffy-coat and cDNA was obtained by reverse-transcription PCR using SuperScript First-Strand Synthesis System. The amplified products were cloned in pGEM-T vector (Promega) and sequenced on an automated gene-sequencer. Both children and the father have a novel 3 bp AAG-deletion position 1834–1836 nt in FXIII A chain. This mutation causes a lysine 570 deletion in the ß-barrel 1 of Factor XIII A subunit and has not been reported so far. It may lead to protein misfolding resulting in an unstable protein, and low levels of FXIII. The second major change detected in the two siblings was a A/T substitution at position 737 nt causing Tyr204Phe substitution in the two siblings; this was present in the mother in a heterozygous condition. This mutation has been previously reported in FXIII deficiency and linked to increased risk of haemorrhagic stroke in young women and of miscarriages. The compound heterozygosity for Lys570Del and Tyr204Phe substitution observed in both children is the likely cause of Factor XIII deficiency leading to lifelong bleeding condition. In addition to above, the father had Val34Leu polymorphism, previously reported to be associated with resistance to myocardial infarction. This polymorphism is present in ∼20% of white European, 40% of Pima Native American and 13% of South Asian populations. The mother also had a known A/C polymorphism at 1119 nt position for a synonymous Pro332Pro change. We also found 3 other variations in FXIII A chain in this family. The daughter has Glu216Gly and Asp267Asn change in the protein corresponding to alterations at nucleotide 773 (A/G) and 925 (A/G), respectively. The son and mother had a substitution at 1442 nt (T/C) leading to a Leu439Pro change. These variations, Glu216Gly, Asp267Asn and Leu439Pro found in the two children (Leu439Pro also in mother) are present in the catalytic core domain of the Factor XIII A chain. All of the polymorphisms or mutations reported in this study were heterozygous in the studied subjects. FXIII gene mutations and polymorphisms result in a high level of heterogeneity of disease presentation. Other point mutations in the FXIII A catalytic core as well as mutations in ß-barrel 1 region have been described in association with a hemorrhagic state in FXIII deficiency. Our study documents a new 3-bp 1834–1836 nt AAG-deletion (Lys570Del) in association with FXIII deficiency. We suggest that compound heterozygosity for Lys570Del and Tyr204Phe is the cause of FXIII deficiency in our patients. Further structure-function studies will aid in understanding the impact of these amino acid substitutions or deletions on FXIII function and on the associated bleeding diathesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Neutralizing autoantibody against factor XIII A subunit resulted in severe bleeding diathesis with a fatal outcome - characterization of the antibody

2016 ◽  
Vol 14 (8) ◽  
pp. 1517-1520 ◽  
Author(s):  
K. Pénzes ◽  
K. Rázsó ◽  
É. Katona ◽  
A. Kerényi ◽  
M. Kun ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Fatal Outcome ◽  
Severe Bleeding ◽  
Bleeding Diathesis ◽  
A Subunit

Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder

2006 ◽  
Vol 95 (01) ◽  
pp. 77-84 ◽  
Author(s):  
Verena Schroeder ◽  
Esther Meili ◽  
Trinh Cung ◽  
Peter Schmutz ◽  
Hans Kohler
Keyword(s):  
Amino Acid ◽  
Factor Xiii ◽  
Bleeding Disorder ◽  
Single Amino Acid ◽  
Factor Xiiia ◽  
Novel Mutations ◽  
Factor Xiii Deficiency ◽  
Single Amino Acid Change ◽  
A Subunit ◽  
Congenital Factor

SummaryIn 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 del G, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.

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