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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3051-3054.
Prepublished online as a Blood First Edition Paper on December 24, 2003; DOI 10.1182/blood-2003-10-3725.
Submitted October 31, 2003
Accepted December 12, 2003
Missense or splicing mutation? The case of a fibrinogen B -chain mutation causing severe hypofibrinogenemia
Rosanna Asselta, Stefano Duga, Silvia Spena, Flora Peyvandi, Giancarlo Castaman, Massimo Malcovati, Pier M Mannucci, and Maria L Tenchini*
Department of Biology and Genetics for Medical Sciences, University of Milan, Milan, Italy
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Department of Internal Medicine, University of Milan and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Maggiore Hospital, Milan, Italy
Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza, Italy
* Corresponding author; email: marialuisa.tenchini{at}unimi.it.
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 (Arg17ter) in the fibrinogen B -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 B-Leu172Gln fibrinogen was normally assembled and secreted. Inspection of the nucleotide sequence surrounding the mutation suggested a possible role on pre-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 B-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.
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