Molecular characterization of the first missense mutation in the fibrinogen Aalpha-chain gene identified in a compound heterozygous afibrinogenemic patient

Manuela Platé, Rosanna Asselta, Flora Peyvandi, Maria Luisa Tenchini, Stefano Duga

Research output: Contribution to journalArticle

Abstract

Congenital afibrinogenemia is a rare coagulopathy characterized by extremely low levels of functional and immunoreactive fibrinogen in plasma, associated with a hemorrhagic phenotype of variable severity. It is transmitted as an autosomal recessive trait and is invariantly associated with mutations affecting 1 of the 3 fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Most genetic defects causing afibrinogenemia are truncating mutations, whereas only few missense mutations (6) have been identified so far, all located in FGB. In this study, the mutational screening of an afibrinogenemic Italian male identified the first missense mutation (Met51Arg) in FGA leading to afibrinogenemia. The patient was a compound heterozygote for a previously described frameshift mutation (1215delT) in the same gene. Met51Arg involves a residue located at the very beginning of the coiled-coil domain, in a region demonstrated to play a pivotal role in hexamer formation. In-vitro expression experiments showed that Met51Arg strongly reduces secretion of hexameric fibrinogen, whereas traces of not completely assembled trimeric intermediate were found in conditioned media. Western blot analysis on the proband's plasma confirmed the presence in vivo of the trimeric fibrinogen, supporting the hypothesis that Met51Arg prevents the final step of fibrinogen assembly.

Original languageEnglish
Pages (from-to)781-787
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1772
Issue number7
DOIs
Publication statusPublished - Jul 2007

Keywords

  • Aα chain
  • Afibrinogenemia
  • Fibrinogen
  • Missense mutation
  • Protein ex-vivo expression

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Biophysics

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