Missense or splicing mutation? The case of a fibrinogen Bβ-chain mutation causing severe hypofibrinogenemia

Rosanna Asselta, Stefano Duga, Silvia Spena, Flora Peyvandi, Giancarlo Castaman, Massimo Malcovati, Pier Mannuccio Mannucci, Maria Luisa Tenchini

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Abstract

The genetic basis of severe hypofibrinogenemia was analyzed in a 57-year-old Italian woman. She turned out to be a compound heterozygote for a novel putative missense mutation (Leu172Gln) and a previously described nonsense mutation (Arg17Stop) in the fibrinogen Bβ-chain gene. The pathogenetic role of Leu172Gln was analyzed by in vitro expression of the mutant recombinant protein in COS-1 cells. These experiments demonstrated that mutant Bβ-Leu172Gln fibrinogen was normally assembled and secreted. Inspection of the nucleotide sequence surrounding the mutation suggested a possible role on pre-messenger RNA (mRNA) splicing. Production of the mutant transcript in HeLa cells confirmed that the mutation activates a cryptic acceptor splice site in exon 4, resulting in a truncated Bβ chain, lacking approximately 70% of the C-terminal region. This represents the first exonic splicing mutation identified in the fibrinogen genes. These findings strengthen the importance to analyze potentially pathogenetic nucleotide variations at both the protein and the mRNA level.

Original languageEnglish
Pages (from-to)3051-3054
Number of pages4
JournalBlood
Volume103
Issue number8
DOIs
Publication statusPublished - Apr 15 2004

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ASJC Scopus subject areas

  • Hematology

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