Abstract
ABSTRACTObjective: To study the gene mutation of human coagulation factor XII (FXII) in a Chinese family with FXII deficiency and it will help us to understand the pathogenesis of this type of disease.Clinical presentation: The proband was a 50-year-old male who had a fracture of the right humerus. The routine presurgical coagulation test showed a significant prolonged activated partial thromboplastin time (APTT) at 59.1s (reference range, 29.0–43.0s).Techniques: FXII activity (FXII:C) and FXII antigen (FXII:Ag) were detected by the one-stage clotting method and ELISA, respectively. To identify mutations, the FXII whole exon and flanking sequences were carried out. Suspected mutations were confirmed by reverse sequencing. The conservatism and possible impact of the amino acid substitution were analyzed by ClustalX-2.1-win and four online bioinformatics tools.Results: Phenotypic analysis revealed the FXII:C and FXII:Ag of the proband were 4% and 5%, respectively (normal range, 72–113%). Gene sequencing detected compound heterozygous mutations c.1561G > A (Glu502Lys) and c.1637T > C (Met527Thr) in exon 13. Bioinformatics and model analysis indicated that mutations probably had disrupted the function and structure of the FXII protein.Conclusion: We detected two missense mutations Glu502Lys and Met527Thr in the catalytic domain of the proband, of which Met527Thr was first reported in the world. Our findings suggest that the double mutations in the FXII gene were the causing reasons for the decreased FXII:C and FXII:Ag. These results not only enriched the F12 mutation database in this condition, but also helped to identify the genetic defects of FXII in China.
Highlights
Human coagulation factor XII (FXII) is a serine protease precursor mainly synthesized by the liver
The FXII:Ag was detected by enzyme linked immunosorbent assay (ELISA) kit (Changfeng, Wenzhou, China), in which polyclonal goat anti-human FXII IgG was used as coating antibody and monoclonal peroxidase-conjugated goat anti-human FXII IgG was used as detecting antibody
Except the activated partial thromboplastin time (APTT) was raised at 59.1s, and FIB was slightly raised at 4.44 g/L, other indexes such as the platelet levels, prothrombin time (PT), thrombin time (TT) were within normal ranges
Summary
Human coagulation factor XII (FXII) is a serine protease precursor mainly synthesized by the liver. The mature protein consisting of 596 amino acid residues, has a concentration of 30–35 ug mL−1 in circulating plasma and a half-life of 50–70 h [1]. The gene encoding FXII is 12 kb in size, located on the chromosome 5q33qter and consists of 14 exons. FXII plays an important role in initiating the endogenous pathway of blood coagulation. When it contacts the negatively charged surface in vitro, the attached precursor is cleaved by kallikrein at Arg353-Val354, which in turn activates more FXII protein [2,3]. Activated FXII (FXIIa) initiates the endogenous coagulation pathway, and participates in activation of the fibrinolysis pathway, complement activation, and inflammatory response [4–6]
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