Yessine Amri1, Choumous Kallel2, Mariem Becheur3, Rym Dabboubi4, Moez Elloumi5, Hatem Belaaj5, Sami Kammoun6, Taieb Messaoud4, Philippe de Moerloose7, Nour El Houda Toumi8. 1. Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia. Electronic address: amri.yessine@yahoo.com. 2. Hematology Laboratory, Habib Bourguiba University Hospital, Sfax, Tunisia. 3. Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia. 4. Biochemistry Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia. 5. Hematology Laboratory, Hedi Chaker University Hospital, Sfax, Tunisia. 6. Department of Pneumology, Hedi Chaker University Hospital, Sfax, Tunisia. 7. Division of Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland. 8. Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia; Department of Clinical Biology A, Faculty of Pharmacy, Monastir, Tunisia.
Abstract
BACKGROUND: Congenital disorders of fibrinogen are rare diseases resulting in the complete absence (afibrinogenemia), reduced concentration (hypofibrinogenemia) or altered function of circulating fibrinogen (dysfibrinogenemia). A combination of two different fibrinogen abnormalities with a significant functional and secretion defect (hypodysfibrinogenemia) reported in Tunisian family members, was investigated in this study. METHODS: The coagulation-related tests, kinetics of fibrin polymerization and lysis and fibrinogen analysis using gel electrophoresis were performed in the family members to characterize fibrinogen abnormalities. All exons including exon-intron boundaries of fibrinogen genes were screened by direct sequencing. RESULTS: Mutational screening of the fibrinogen genes disclosed novel missense mutations, BβCys197Arg, in exon 4 of the fibrinogen Bβ-chain gene. After the loose of its partner in Bβ-chain, the γCys135 was probably disulfide-bridged to its corresponding Cys residue of another abnormal fibrinogen molecule, forming dimmer with an abnormal electrophoretic profile. Homozygous form carried by the proband found to be directly involved in the bleeding phenotype by affecting fibrin polymerization. In contrast, affected family members bearing the heterozygous mutation showed an impaired fibrin polymerization and fibrinolysis leading to thrombosis. CONCLUSION: These results suggest that this mutation could alter the extremely conserved conformations of fibrinogen D domain and D-D lateral regions on fibrin assembly.
BACKGROUND:Congenital disorders of fibrinogen are rare diseases resulting in the complete absence (afibrinogenemia), reduced concentration (hypofibrinogenemia) or altered function of circulating fibrinogen (dysfibrinogenemia). A combination of two different fibrinogen abnormalities with a significant functional and secretion defect (hypodysfibrinogenemia) reported in Tunisian family members, was investigated in this study. METHODS: The coagulation-related tests, kinetics of fibrin polymerization and lysis and fibrinogen analysis using gel electrophoresis were performed in the family members to characterize fibrinogen abnormalities. All exons including exon-intron boundaries of fibrinogen genes were screened by direct sequencing. RESULTS: Mutational screening of the fibrinogen genes disclosed novel missense mutations, BβCys197Arg, in exon 4 of the fibrinogen Bβ-chain gene. After the loose of its partner in Bβ-chain, the γCys135 was probably disulfide-bridged to its corresponding Cys residue of another abnormal fibrinogen molecule, forming dimmer with an abnormal electrophoretic profile. Homozygous form carried by the proband found to be directly involved in the bleeding phenotype by affecting fibrin polymerization. In contrast, affected family members bearing the heterozygous mutation showed an impaired fibrin polymerization and fibrinolysis leading to thrombosis. CONCLUSION: These results suggest that this mutation could alter the extremely conserved conformations of fibrinogen D domain and D-D lateral regions on fibrin assembly.
Authors: Brenton J Francisco; Bal Krishan Sharma; Hannah M Russell; Leah Rosenfeldt; A Phillip Owens; Matthew J Flick; Eric S Mullins; Joseph Palumbo Journal: Blood Adv Date: 2022-07-26