title: Hypodysfibrinogenemia: A novel abnormal fibrinogen associated with bleeding and thrombotic complications.
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.
  
  
  CONCLUSIONS
  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.affiliation: Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia. Electronic address: amri.yessine@yahoo.com.
authors.forename: Yessine
authors.initials: Y
authors.lastname: Amri
authors.affiliation: Hematology Laboratory, Habib Bourguiba University Hospital, Sfax, Tunisia.
authors.forename: Choumous
authors.initials: C
authors.lastname: Kallel
authors.affiliation: Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
authors.forename: Mariem
authors.initials: M
authors.lastname: Becheur
authors.affiliation: Biochemistry Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
authors.forename: Rym
authors.initials: R
authors.lastname: Dabboubi
authors.affiliation: Hematology Laboratory, Hedi Chaker University Hospital, Sfax, Tunisia.
authors.forename: Moez
authors.initials: M
authors.lastname: Elloumi
authors.affiliation: Hematology Laboratory, Hedi Chaker University Hospital, Sfax, Tunisia.
authors.forename: Hatem
authors.initials: H
authors.lastname: Belaaj
authors.affiliation: Department of Pneumology, Hedi Chaker University Hospital, Sfax, Tunisia.
authors.forename: Sami
authors.initials: S
authors.lastname: Kammoun
authors.affiliation: Biochemistry Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
authors.forename: Taieb
authors.initials: T
authors.lastname: Messaoud
authors.affiliation: Division of Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: de Moerloose
authors.affiliation: Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia; Department of Clinical Biology A, Faculty of Pharmacy, Monastir, Tunisia.
authors.forename: Nour El Houda
authors.initials: Nel H
authors.lastname: Toumi
mesh_terms: D000347:Afibrinogenemia / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005340:Fibrinogen / Q000235:genetics; D015241:Fibrinogens, Abnormal / Q000235:genetics*; D005838:Genotype; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D013927:Thrombosis / Q000235:genetics; D014416:Tunisia
chemical_list: C115499:BBeta fibrinogen; D015241:Fibrinogens, Abnormal; D005340:Fibrinogen
keywords: Bleeding; Fibrinolysis; Hypodysfibrinogenemia; Missense mutation; Polymerization; Thrombosis