A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia
Kaiqi Jia
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
2
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang, People's Republic of China
,
Manlin Zeng
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
,
Xiaoyong Zheng
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
,
Haixiao Xie
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
,
Lihong Yang
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
,
Yaosheng Xie
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
,
Mingshan Wang
1
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
2
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang, People's Republic of China
› Author AffiliationsFunding This work was funded by the Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (2022E10022) and the Science and Technology Plan Fund of Wenzhou (Y20220746).
Objective Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis.
Methods The one-stage clotting method was used to test the fibrinogen activity (FIB:C), whereas immunoturbidimetry was performed to quantify the fibrinogen antigen (FIB:Ag). Furthermore, DNA sequence analysis was conducted to confirm the site of mutation. Conservation analysis and protein model analysis were performed using online bioinformatics software.
Results The FIB:C and FIB:Ag of the proband were 1.28 and 2.20 g/L, respectively. Gene analysis revealed a heterozygous c.293C > A (p.BβAla68Asp) mutation in FGB. Bioinformatics and modeling analysis suggested that the missense mutation could potentially have a deleterious effect on fibrinogen.
Conclusion The BβAla68Asp mutation in exon 2 of FGB may account for the reduced FIB:C levels observed in the pedigree. To our knowledge, this point mutation is the first report in the world.
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
References
1
Luo S,
Xu Q,
Xie Y.
et al.
A novel heterozygous mutation (γIIe367Thr) causes congenital dysfibrinogenemia in a Chinese family. Blood Coagul Fibrinolysis 2020; 31 (08) 569-574
2
Li S,
Wang M,
Li X.
et al.
Analysis of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the FGA gene. Hamostaseologie 2020; 40 (05) 642-648
4
Tajdar M,
Orlando C,
Casini A.
et al.
Heterozygous FGA p.Asp473Ter (fibrinogen Nieuwegein) presenting as antepartum cerebral thrombosis. Thromb Res 2018; 163: 185-189
6
Casini A,
de Moerloose P,
Neerman-Arbez M.
Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42 (04) 366-374
7
Casini A,
Neerman-Arbez M,
Ariëns RA,
de Moerloose P.
Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (06) 909-919
13
Meh DA,
Mosesson MW,
Siebenlist KR.
et al.
Fibrinogen Naples I (B beta A68T) nonsubstrate thrombin-binding capacities. Thromb Res 2001; 103 (01) 63-73
14
Casini A,
Lukowski S,
Quintard VL.
et al.
FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations. Thromb Res 2014; 133 (05) 868-874
15
Ceznerová E,
Kaufmanová J,
Sovová Ž.
et al.
Structural and functional characterization of four novel fibrinogen mutations in FGB causing congenital fibrinogen disorder. Int J Mol Sci 2022; 23 (02) 23
17
Lord ST,
Strickland E,
Jayjock E.
Strategy for recombinant multichain protein synthesis: fibrinogen B beta-chain variants as thrombin substrates. Biochemistry 1996; 35 (07) 2342-2348
18
Mullin JL,
Gorkun OV,
Lord ST.
Decreased lateral aggregation of a variant recombinant fibrinogen provides insight into the polymerization mechanism. Biochemistry 2000; 39 (32) 9843-9849
19
Yoshida S,
Kibe T,
Matsubara R.
et al.
Congenital dysfibrinogenemia in a Japanese family with fibrinogen Naples (BβAla68Thr) manifesting as superior sagittal sinus thrombosis. Blood Coagul Fibrinolysis 2017; 28 (07) 580-584
20
Pechik I,
Madrazo J,
Mosesson MW,
Hernandez I,
Gilliland GL,
Medved L.
Crystal structure of the complex between thrombin and the central “E” region of fibrin. Proc Natl Acad Sci U S A 2004; 101 (09) 2718-2723
