title: Congenital afibrinogenemia: Identification and characterization of two novel homozygous fibrinogen Aα and Bβ chain mutations in two Tunisian families.
abstract: BACKGROUND
  Inherited abnormalities of fibrinogen (FG) are rare coagulation disorders divided into two types: quantitative abnormalities (afibrinogenemia and hypofibrinogenemia) or qualitative abnormalities (dysfibrinogenemia and hypo-dysfibrinogenemia) of circulating fibrinogen. In particular, congenital afibrinogenemia is inherited as an autosomal recessive mode and is usually determined by homozygous or compound heterozygous mutations affecting any of the three fibrinogen genes (FGA, FGB and FGG), resulting in the complete absence or extremely reduced amount of fibrinogen. The aim of the present study was to characterize the fibrinogen abnormalities in two Tunisian families.
  
  
  METHODS
  Coagulation studies were performed on the patients and family members. All the exons and the flanking intron regions of fibrinogen genes were screened by direct sequencing.
  
  
  RESULTS
  Probands had concomitant bleeding complications with infinitely prolonged standard coagulation assays. Mutational screening of the fibrinogen gene cluster of each proband, disclosed two previously undescribed homozygous point mutations. The first mutation was a major truncation (AαArg252Stop) leads to a severe premature termination codon in the exon 5 of the FGA gene. This mutation defines in vivo the importance of the αC flexible segment in the secretion of a stable fibrinogen molecule. The second afibrinogenemic mutation (BβGly295Ala) occurs in the exon 7 of the FGB gene. This missense mutation would probably lead to significant conformational change not allowing the expression of the fibrinogen protein.
  
  
  CONCLUSIONS
  Current molecular characterization of these two fibrinogen abnormalities confirms the importance of the first portion of αC-region (αC-connector) as well as the Bβ globular domain in the secretion processes.
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, 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
authors.affiliation: Biochemistry Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
authors.forename: Sondess
authors.initials: S
authors.lastname: Hadj Fredj
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
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D001777:Blood Coagulation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D014416:Tunisia / Q000453:epidemiology; D055815:Young Adult
chemical_list: C115499:BBeta fibrinogen; C464794:fibrinogen Aalpha; D005340:Fibrinogen
keywords: Blood coagulation; Congenital afibrinogenemia; Fibrinogen; Missense mutation; Nonsense mutation