Congenital afibrinogenemia: Identification and characterization of two novel homozygous fibrinogen Aα and Bβ chain mutations in two Tunisian families

- Two novel homozygous mutations were found to be associated with severe bleeding.
- Both mutations were found to be the cause of congenital afibrinogenemia.
- The first mutation (AαArg252Stop) is situated in the αC flexible segment.
- The second mutation (BβGly295Ala) is situated in the Bβ globular domain.

IntroductionInherited 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.MethodsCoagulation 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.ResultsProbands 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.ConclusionCurrent 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.