Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (<i>FGA</i>c.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization

Zhou, Junju; Ding, Qiulan; Wu, Wenman; Ouyang, Qi; Xie, Yinyin; Wu, Xi; Lu, Yiming; Dai, Jing; Liang, Qian; Wang, Hongli; Wang, Xuefeng; Hu, Yiqun

doi:10.1136/jclinpath-2016-203862

Cited by 5 publications

(2 citation statements)

References 27 publications

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“…Routine coagulation tests, including prothrombin time, activated partial thromboplastin time, thrombin time and the fibrinogen activity, were carried out with citrated plasma samples on a Sysmex-7000 coagulation analyser. Thrombophilia screening tests, including the activities of PC, PS and antithrombin, as well as lupus anticoagulant, anticardiolipin antibody, anti-β2 glycoprotein 1 and total homocysteine, were assayed as described previously 23. The qualitative analysis of total PS (TPS) level in plasma were detected by western blot using a rabbit polyclonal anti-human PS antibody (Abcam, Cambridge, Massachusetts, USA).…”

Section: Methodsmentioning

confidence: 99%

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

Zhou

Shen

et al. 2019

J Clin Pathol

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AimsHereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type I PS deficiency with compound heterozygous mutations of PROS1 gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of PROS1 mutations causing PS deficiency.MethodsGenetic analysis of PROS1 gene was carried out by direct sequencing. Thrombin generation potential and the inhibition function of thrombin generation by plasma PS were detected by thrombin generation test (TGT). The mRNA transcription level of mutant PS in vitro was measured by real-time PCR, while the protein level was evaluated by western blot and ELISA. Cellular distribution of the protein was further analysed by immunofluorescence.ResultsCompound heterozygous mutations (PROS1 c.1551_1552delinsG, p.Thr518Argfs*39 and PROS1 c.1681C>T, p.Arg561Trp) were identified in the propositus, and the former one was a novel small indel mutation. TGT results showed impaired inhibition of thrombin generation with the addition of activated protein C in his parents with certain heterozygous mutations. In vitro expression study, p.Thr518Argfs*39 mutant produced truncated protein retained in the cytoplasm, while p.Arg561Trp mutant partially affected the secretion of PS. Both mutations are located in C-terminal sex hormone-binding globulin (SHBG)-like domain of PS.ConclusionsCompound heterozygous mutations identified in the study have strong detrimental effect, causing severe type I PS deficiency in the propositus. SHBG-like domain of PS might play an important role in PS secretion system.

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Section: Methodsmentioning

confidence: 99%

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

Zhou

Shen

et al. 2019

J Clin Pathol

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“…Scanning electron microscopy observations of the fibrin from the proband suggested that the strength, structure, and stability of fibrin might be impaired. Consequently, the clot formed by such fibrin is more permeable and less likely to effectively entangle platelets and other blood cells, resulting in reduced hemostasis and an elevated risk of bleeding compared to healthy individuals [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

A novel mutation in the FGG gene causes hypofibrinogenemia in a Chinese family

Xie,

Du,

Geng

et al. 2024

Hereditas

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Congenital fibrinogen disorders are a group of coagulation deficiencies caused by fibrinogen defects and are divided into four types, including afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. In this study, we collected a family with hypofibrinogenemia, and genetics analysis identify a novel pathogenic variants (c.668G > C, p.Arg223Thr) in the FGG gene. And electron microscope observation revealed significant changes in the ultrastructure of fibrin of the proband. Our research expands the phenotypic and genetic spectrum associated with the FGG gene, which would facilitate in genetic counselling and prenatal genetic diagnosis.

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Fibrinogen BOE II: dysfibrinogenemia with bleeding and defective thrombin binding

Li¹,

Liang²,

Wu³

et al. 2023

Research and Practice in Thrombosis and Haemostasis

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Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGAc.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization

Abstract: Fibrinogen Shanghai results in N-terminal truncation of Aα chain, which does not interfere with synthesis, assembly or secretion of fibrinogen, but compromises fibrin polymerization and clot formation. APS at least partially contributes to the development of thrombosis in the propositus.

Cited by 5 publications

References 27 publications

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

A novel mutation in the FGG gene causes hypofibrinogenemia in a Chinese family

Fibrinogen BOE II: dysfibrinogenemia with bleeding and defective thrombin binding

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