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Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGA c.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization
  1. Jingyi Zhou1,
  2. Qiulan Ding2,
  3. Wenman Wu2,
  4. Qi Ouyang3,
  5. Yinyin Xie1,
  6. Xi Wu2,
  7. Yeling Lu2,
  8. Jing Dai2,
  9. Qian Liang2,
  10. Hongli Wang1,
  11. Xuefeng Wang2,
  12. Yiqun Hu4
  1. 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  2. 2Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  3. 3Department of Laboratory Medicine, Eye and Ear Nose Throat (ENT) Hospital, Shanghai Medical School, Fudan University, Shanghai, China
  4. 4Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  1. Correspondence to Professor Xuefeng Wang, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine. No.197 Ruijin Second Road, Shanghai 200025, China; wangxuefeng6336{at}hotmail.com and Professor Yiqun Hu, Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine. No.197 Ruijin Second Road, Shanghai 200025, China; ichunhu{at}126.com

Abstract

Aims A novel heterozygous variant, FGA c.169_180+2 del (designated fibrinogen Shanghai), was identified in a patient with dysfibrinogenemia with antiphospholipid antibody syndrome (APS) and recurrent venous thrombosis, and in his asymptomatic father. We aimed to reveal the functional implication of structural change caused by this variant.

Methods Transcription analysis was performed with FGA minigene transfection assay to evaluate the impact of nucleosides deletion on mRNA editing. The fibrinogen isolated from propositus' plasma was used to characterise its functional defects. Fibrin polymerization and clot lysis experiments were performed by optical measurement of turbidity. Thrombin-catalysed fibrinopeptide release was analysed by the reversed-phase, high-performance liquid chromatography. The ultrastructures of fibrin clots were visualised by scanning electron microscopy.

Results FGA c.169_180+2 del led to an aberrant mRNA with exon 2 skipping and encoded an shortened Aα chain with 42 amino acids truncation at its N-terminal. The propositus' fibrinogen had an impaired release of fibrinopeptide A and abnormal polymerization with a significantly prolonged lag time, a slower maximum slope and reduced final turbidity. The fibrin clot formed with propositus' fibrinogen showed thicker fibres with looser network structure. Clot lysis was normal using the purified fibrinogen but was significantly impaired using the plasma sample from propositus, compared with that from his father.

Conclusions 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.

  • FIBRINOGEN
  • HAEMOSTASIS
  • GENETICS

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