Phenotypic and genetic analyses of four cases of coagulation factor XII deficiency

ABSTRACT

Objectives

To identify the clinical phenotypic and molecular pathogeneses of four cases of coagulation factor XII deficiency and to deepen the cognition of this disease.

Methods

Coagulation tests were performed through one stage of coagulation on a STAGO coagulation analyser. Coagulation factor XII antigen was detected using enzyme-linked immunosorbent assay. The species conservatism and structural change of mutant proteins were analysed using MegAlign and PYMOL. Meanwhile, missense variants and a novel splice site variant were identified using PolyPhen2 and NetGene2.

Results

The four cases had an observably prolonged activated partial thromboplastin time but without obvious bleeding tendency. Their coagulation factor XII activity (FⅫ:C) and antigen (FXII:Ag) were greatly reduced. Six mutations were detected: NM_000505.4:c.398-1G>A, NP_000496.2:p.(Pro182Leu), NP_000496.2:p.(Ser479Ter), NP_000496.2:p.(Cys559Arg), NC_000005.10:g.7217_7221delinsGTCTA and NM_000505.4:c.1681-1G>A. The first five are newly discovered mutations. The two missense mutation sites were highly conservative, and their protein secondary structure changes may occur not only on the mutation sites but also on other domains. In silico analysis revealed that NP_000496.2:p.(Pro182Leu) may be BENIGN, NP_000496.2:p.(Cys559Arg) may be damaging, and that NM_000505.4:c.398-1G>A and NM_000505.4:c.1681-1G>A are crucial for splicing.

Conclusion

We found six types of mutations, of which five were novel. The two missense mutation sites might be closely related to the function of coagulation factor XII. The mutations were the primary culprits of factor XII deficiency.

KEYWORDS:

• Factor XII
• factor XII deficiency
• heterozygote
• mutation
• protein structure

Acknowledgments

Given the limited number of references allowed in this perspective, we wish to thank the colleagues who are not specifically cited for their contribution and their understanding.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the [Public Welfare Science and Technology Projects of Wenzhou City] [grant number Y20210101].

Notes on contributors

Shanshan Li

Shanshan Li works at the Medical Laboratory Center of The Second Affiliated Hospital of Wenzhou Medical University. Their research interests include thrombosis and hemostasis. Shanshan Li’s study mainly involves FXII.

Kuangyi Shu

Kuangyi Shu works at the Medical Laboratory Center of The Second Affiliated Hospital of Wenzhou Medical University. Their research interests include thrombosis and hemostasis.

Fanfan Li

Fanfan Li is a Ph.D. candidate, whose research focuses on thrombosis.

Xiao Yang

Xiao Yang has a master’s degree. His research interests include thrombosis, hemostasis and schizophrenia; and works in Wenzhou Seventh People’s Hospital.

Wei Yang

Wei Yang is a Ph.D. candidate at the School of Laboratory Medicine and Life Science, Wenzhou Medical University. His research interests include thrombosis and hemostasis, and tumor-educated platelets.

Manli Ye

Manli Ye works at The Medical Laboratory Center of the Second Affiliated Hospital of Wenzhou Medical University. Their research interests include thrombosis and hemostasis.

Xiaoou Wang

Xiaoou Wang works at the Medical Laboratory Center of The Second Affiliated Hospital of Wenzhou Medical University. Their research interests include thrombosis and hemostasis.

Minghua Jiang

Minghua Jiang is a Director of Laboratory Medicine and Medical Laboratory Center of The Second Affiliated Hospital of Wenzhou Medical University. His research interests include thrombosis and hemostasis, abnormal platelet function, and tumor-educated platelets.