Analysis of an Inherited Dysfibrinogenemia Pedigree Associated with a Heterozygous Mutation in the FGA Gene

Abstract

Objective This article aims to analyze the phenotype and genotype of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the FGA gene, and to investigate the pathogenesis of this disease.

Clinical Presentation The proband of interest is a 29-year-old woman. She was in her 37 weeks of gestation. Routine coagulation tests showed low fibrinogen activity (0.91 g/L; normal range: 2.0–4.0 g/L) and normal fibrinogen antigen (FIB:Ag) level (2.09 g/L; normal range: 2.0–4.0 g/L).

Techniques The prothrombin time, activated partial thromboplastin time, thrombin time, and activity of plasma fibrinogen (FIB:C) were detected by the one-stage clotting method. The FIB:Ag, D-dimer, and fibrinogen degradation products were tested by the immunoturbidimetry method. To identify the novel missense mutation, fibrinogen gene sequencing and molecular modeling were performed. We used ClustalX-2.1-win and online bioinformatic software to analyze the conservation and possible effect of the amino acid substitution on fibrinogen.

Results Phenotypic analysis revealed that the FIB:C of the proband was significantly reduced while the FIB:Ag was normal. Sequencing analysis detected a heterozygous C.2185G > A point mutation in the FGA gene (AαGlu710Lys). Bioinformatic and modeling analyses indicated that the mutation probably caused harmful effects on fibrinogen.

Conclusion The heterozygous mutation of Glu710Lys in the FGA gene was identified that could cause the reduction of the FIB structure stability and result in the dysfibrinogenemia.

Keywords

fibrinogen - dysfibrinogenemia - FGA - novel mutation

Authors' Contributions

All authors have made substantial contributions to the conception and design of the study, acquisition of data, 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.

Ethics Approval

Our study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (China).

Publication History

Received: 20 April 2020

Accepted: 10 September 2020

Article published online:
29 December 2020

• References

• 1 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
• 2 Spraggon G, Everse SJ, Doolittle RF. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature 1997; 389 (6650): 455-462
• 3 Smith N, Bornikova L, Noetzli L. et al. Identification and characterization of novel mutations implicated in congenital fibrinogen disorders. Res Pract Thromb Haemost 2018; 2 (04) 800-811
• 4 Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann N Y Acad Sci 2001; 936: 11-30
• 5 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3 (08) 1894-1904
• 6 Zhou N, Xu P, Zhou M. et al. A novel fibrinogen variant: dysfibrinogenemia associated with γAsp185Asn substitution. J Thromb Thrombolysis 2017; 44 (01) 139-144
• 7 Zhou J, Zhu P, Zhang X. A Chinese family with congenital dysfibrinogenemia carries a heterozygous missense mutation in FGA: concerning the genetic abnormality and clinical treatment. Pak J Med Sci 2017; 33 (04) 968-972
• 8 Zhang H, Luo S, Fang W. et al. Phenotypic and genetic analysis of hypofibrinogenemia because of a novel missense mutation in the FGB: Leu121Arg. Blood Coagul Fibrinolysis 2019; 30 (05) 233-238
• 9 Lishko VK, Yakubenko VP, Hertzberg KM, Grieninger G, Ugarova TP. The alternatively spliced alpha(E)C domain of human fibrinogen-420 is a novel ligand for leukocyte integrins alpha(M)beta(2) and alpha(X)beta(2). Blood 2001; 98 (08) 2448-2455
• 10 Fu Y, Weissbach L, Plant PW. et al. Carboxy-terminal-extended variant of the human fibrinogen α subunit: a novel exon conferring marked homology to β and γ subunits. Biochemistry 1992; 31 (48) 11968-11972
• 11 Hanss M, Biot F. A database for human fibrinogen variants. Ann N Y Acad Sci 2001; 936: 89-90
• 12 Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42 (04) 366-374
• 13 Protopopova AD, Litvinov RI, Galanakis DK. et al. Morphometric characterization of fibrinogen's αC regions and their role in fibrin self-assembly and molecular organization. Nanoscale 2017; 9 (36) 13707-13716
• 14 Westbury SK, Duval C, Philippou H. et al. Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis. Thromb Haemost 2013; 110 (06) 1135-1144
• 15 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann N Y Acad Sci 2001; 936: 480-495
• 16 Weisel JW, Medved L. The structure and function of the alpha C domains of fibrinogen. Ann N Y Acad Sci 2001; 936: 312-327
• 17 Mukaddam A, Kulkarni B, Jadli A, Ghosh K, Shetty S. Spectrum of mutations in Indian patients with fibrinogen disorders and its application in genetic diagnosis of the affected families. Haemophilia 2015; 21 (06) e519-e523
• 18 Zhou J, Ding Q, Chen Y. et al. Clinical features and molecular basis of 102 Chinese patients with congenital dysfibrinogenemia. Blood Cells Mol Dis 2015; 55 (04) 308-315