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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

Fingerprint

Fibrinogen
Mutation
Nucleotides
Genes
RNA Splicing
Messenger RNA
RNA Splice Sites
Nonsense Codon
COS Cells
Missense Mutation
Mutant Proteins
Heterozygote
HeLa Cells
Recombinant Proteins
Exons
Inspection
Proteins
Experiments
In Vitro Techniques

ASJC Scopus subject areas

  • Hematology

Cite this

Missense or splicing mutation? The case of a fibrinogen Bβ-chain mutation causing severe hypofibrinogenemia. / Asselta, Rosanna; Duga, Stefano; Spena, Silvia; Peyvandi, Flora; Castaman, Giancarlo; Malcovati, Massimo; Mannucci, Pier Mannuccio; Tenchini, Maria Luisa.

In: Blood, Vol. 103, No. 8, 15.04.2004, p. 3051-3054.

Research output: Contribution to journalArticle

Asselta, Rosanna ; Duga, Stefano ; Spena, Silvia ; Peyvandi, Flora ; Castaman, Giancarlo ; Malcovati, Massimo ; Mannucci, Pier Mannuccio ; Tenchini, Maria Luisa. / Missense or splicing mutation? The case of a fibrinogen Bβ-chain mutation causing severe hypofibrinogenemia. In: Blood. 2004 ; Vol. 103, No. 8. pp. 3051-3054.
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AU - Castaman, Giancarlo

AU - Malcovati, Massimo

AU - Mannucci, Pier Mannuccio

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