scholarly journals Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257322
Author(s):  
Tsukasa Osaki ◽  
Masayoshi Souri ◽  
Akitada Ichinose
Keyword(s):  
Factor Xiii ◽  
Coagulation Factor ◽  
Human Leukocyte ◽  
Sequencing Analysis ◽  
Factor Xiii Deficiency ◽  
Leukocyte Antigen ◽  
Coagulation Factor Xiii ◽  
Whole Exome ◽  
Variant Alleles ◽  
Fxiii Deficiency

Autoimmune coagulation factor XIII deficiency is a bleeding disorder caused by the formation of autoantibodies against the coagulation factor XIII (FXIII); however, the molecular mechanism underlying this process is unknown. Therefore, in the present study, we aimed to elucidate this mechanism by performing whole-exome sequencing analysis of 20 cases of autoimmune FXIII deficiency. We identified approximately 21,788–23,916 variants in each case. In addition to their ability to activate T cells, present antigens, and immune tolerance, the candidate alleles were further narrowed down according to their allelic frequencies and the magnitude of damage caused by the substitution of amino acids. After selecting 44 candidate alleles, we investigated whether they were associated with the FXIII inhibitory titers and/or the anti-FXIII autoantibodies. We found that two polymorphisms whose variant allele frequencies were significantly lower in the patients tended to decrease FXIII inhibitory titers as the number of variant alleles increased. We also found that five polymorphisms whose variant allele frequencies were significantly higher in the patients tended to increase the levels of the anti-FXIII autoantibodies as the number of variant alleles increased. All of these polymorphisms were found in the human leukocyte antigen (HLA) class I and II molecules and their associated genes. In particular, the HLA class II molecule and its associated genes were found to be involved in the presentation of foreign antigens as well as the negative regulation of the proliferation of T-cells and the release of cytokines. Polymorphisms in the HLA class II molecules and the cytotoxic T lymphocyte antigen 4 have been reported to be associated with the development of autoantibodies in acquired hemophilia A. Therefore, we hypothesized that these polymorphisms may be associated with the development of autoantibodies in autoimmune FXIII deficiency.

Coagulation factor XIII deficiency

2014 ◽  
Vol 34 (02) ◽  
pp. 160-166 ◽  
Author(s):  
V. Ivaskevicius ◽  
A. Thomas ◽  
J. Oldenburg ◽  
A. Biswas
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Coagulation Disorder ◽  
Factor Xiii Deficiency ◽  
Disease States ◽  
Coagulation Factor Xiii ◽  
Cross Links ◽  
Bleeding Episodes ◽  
Fxiii Deficiency

SummaryThe plasma circulating zymogenic coagulation factor XIII (FXIII) is a protransglutaminase, which upon activation by thrombin and calcium cross-links preformed fibrin clots/fibrinolytic inhibitors making them mechanically stable and less susceptible to fibrinolysis. The zymogenic plasma FXIII molecule is a heterotetramer composed of two catalytic FXIII-A and two protective FXIII-B subunits. Factor XIII deficiency resulting from inherited or acquired causes can result in pathological bleeding episodes. A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency. The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it. Recently however, with a growing understanding into the pleiotropic roles of FXIII, the fairly frequent milder form of FXIII deficiency caused by heterozygous mutations has become one of the subjects of investigative research. The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation. Here, we update the knowledge about the pathophysiology of factor XIII deficiency and its therapeutic options.

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

A Novel Nonsense Mutation of F13A1 Gene Causing Inherited Factor XIII Deficiency in a Chinese Han Family

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4661-4661
Author(s):  
Dawei Wang ◽  
Liang Tang ◽  
Wei Shi ◽  
Heng Mei ◽  
Rui Yang ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Factor Xiii ◽  
Family Members ◽  
Coagulation Factor ◽  
Maternal Grandmother ◽  
Chinese Han ◽  
Factor Xiii Deficiency ◽  
Fxiii Activity ◽  
Fxiii Deficiency

Abstract Abstract 4661 Introduction: Coagulation factor XIII (FXIII) is a protransglutaminase that has a major role in the final stage of blood coagulation process by forming cross-links between γ-glutamyl and ε-lysine residues of fibrin chains. The plasma FXIII (pFXIII) circulates in plasma as a heterotetramer (FXIII-A2B2) consisting of two catalytic A subunits (FXIII-A2) and two carrier B subunits (FXIII-B2). Inherited FXIII deficiency is a rare autosomal recessive disease with lifelong bleeding. Most cases of FXIII deficiency are heterogeneous due to mutations in the F13A gene. Currently, more than 100 mutations have been reported. Aim: To identify the genetic defect of inherited coagulation factor XIII (FXIII) deficiency in a Chinese Han family. Methods and Results: A 13 year-old patient complained of poor wound healing after operation and had a history of an excessive bleeding from the umbilical cord stump after her birth. The routine laboratory tests are normal. Her bleeding time is more than 15 minutes and fibrin clot was solubilized very quickly in 5mol/L urea, and became insoluble when normal plasma was mixed with her plasma in vitro. Her plasma FXIII activity was zero with the amine incorporation assay and plasma FXIII antigen was also near zero by one-step sandwich ELISA method, the plasma FXIIIA antigen was zero using an indirect competitive ELISA assay. The plasma FXIIIA antigen, FXIII activity and antigen were assayed in all available family members. The testing results of patient’s grandfather and maternal grandmother were within normal range. But the other pedigree members’ results were lower in different level compare with normal ranges. All members of her family had normal coagulation test. All the exons of F13A gene as well as F13B gene and their flanking regions were amplified by PCR for direct sequencing to identify the mutations in the proband. Direct DNA sequencing of all purified amplification products from the patient’s F13A gene demonstrated a homozygous nonsense mutation in exon8 (C to A transversion at nucleotide 98531 which caused Cys327X). And the patient didn’t have the Val34Leu polymorphism. In the pedigree except of the proband, the Cys327X mutation was found in the heterozygous state in all investigated members except for her grandfather and maternal grandmother. A family study revealed that the mutation was inherited from both parents. The identified mutation was validated by PCR-RFLP technique in the family members and healthy people. Restriction enzyme analysis of amplified exon 8 DNA fragment confirmed that the patient was homozygous for this mutation. Then the quantitative RT-PCR method was used for studying the mRNA expression level of mutant FXIIIA. And the results indicated that F13A mRNA transcripts in heterozygous mutant were reduced by 25% when compared to transcripts in wild-type one, while the homozygous mutant level of F13A mRNA transcript was nearly zero relative to the normal transcript. Conclusion: We have identified a novel Cys327X nonsense mutation in human FXIIIA gene which we have not found in the FXIII database (www.f13-database.de) or in previous publications.And the identified nonsense mutation is causative for severe factor XIII deficiency with a bleeding disorder. Further, in vitro expression studies of the factor XIII mutation is required to confirm their pathological mechanism. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel deep intronic mutation in the coagulation factor XIII a chain gene leading to unexpected RNA splicing in a patient with factor XIII deficiency

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Deng ◽  
Dan Li ◽  
Heng Mei ◽  
Liang Tang ◽  
Hua-fang Wang ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Premature Termination ◽  
Coagulation Factor ◽  
Premature Termination Codon ◽  
Termination Codon ◽  
Chinese Family ◽  
Acceptor Site ◽  
Coagulation Factor Xiii ◽  
Fxiii Deficiency

Abstract Background Coagulation factor XIII (FXIII) plays an essential role in maintaining hemostasis by crosslinking fibrin. Deficiency in FXIII affects clot stability and increases the risk of severe bleeding. Congenital FXIII deficiency is a rare disease. Recently, we identified a Chinese family with FXIII deficiency and investigated the pathogenesis of congenital FXIII deficiency, contributing non-coding pathogenic variants. Methods We performed common tests, coding sequencing by targeted next-generation sequencing (NGS), whole-genome sequencing and splice-sites prediction algorithms. The pathogenesis was investigated via minigene and nonsense-mediated mRNA decay (NMD) by experiments in vitro. Results The proband is homozygote for a novel deep intronic c.799-12G > A mutation in the F13A1 gene. Through direct sequencing of the minigenes mRNA, we found 10 bases of intron 6 insert in the mRNA of mutant minigenes mRNA. The relative expression of EGFP-F13A1 was higher by suppression of NMD in vitro. Furthermore, we found the proband with enhanced thrombin generation (TG). Conclusion We reported a novel deep intronic c.799-12G > A mutation of F13A1 which produced a new acceptor site and frame shifting during translation introducing a premature termination codon. Our results support the premature termination codon triggered NMD. We need to pay attention to the position of potential alterable splicing sites while counselling and genetic test. The finding of enhanced TG indicated that we should be aware of the risk of thrombosis in patients with FXIII deficiency during replacement therapy.

scholarly journals Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family

Hematology ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 501-509 ◽  
Author(s):  
Liwei Sun ◽  
Qijiang Yan ◽  
Yonghua Wang ◽  
Hualei Luo ◽  
Peng Du ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Factor Xiii Deficiency ◽  
Coagulation Factor Xiii
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