Compound heterozygous mutations Glu502Lys and Met527Thr of the FXII gene in a patient with factor XII deficiency

ABSTRACT

Objective: 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.

KEYWORDS:

• Coagulation FXII deficiency
• gene mutation
• novel mutation
• genetic analysis
• polymerase chain reaction
• mutation analysis
• blood coagulation
• prolonged APTT

Acknowledgements

We are grateful to the patient and his family members for cooperation. All authors stated that they had no interests which might be perceived as posing a conflict or bias. All authors have made substantial contributions to the conception and design of the study, acquisition of data, or analysis and interpretation of the data, drafting the article or revising it critically for important intellectual content, and have given their final approval for the version to be submitted.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Science and Technology Department of Zhejiang Province of China under [Grant LGF18H080003].