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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1336-1341
Missense mutations in the human  fibrinogen gene cause
congenital afibrinogenemia by impairing fibrinogen
secretion
Stefano Duga,
Rosanna Asselta,
Elena Santagostino,
Sirous Zeinali,
Tatjana Simonic,
Massimo Malcovati,
Pier Mannuccio Mannucci, and
Maria Luisa Tenchini
From the Department of Biology and Genetics for Medical Sciences,
the Institute of Veterinary Physiology and Biochemistry, the
Angelo Bianchi Bonomi Hemophilia and Thrombosis
Center, and the Fondazione Luigi Villa and the Department of Internal
Medicine, University of Milan; the IRCCS Maggiore Hospital, Milan,
Italy; and the Department of Biotechnology, Pasteur Institute of
Tehran, Iran.
Congenital afibrinogenemia is a rare autosomal recessive disorder
characterized by bleeding that varies from mild to severe and by
complete absence or extremely low levels of plasma and platelet
fibrinogen. Although several mutations in the fibrinogen genes
associated with dysfibrinogenemia and hypofibrinogenemia have been
described, the genetic defects of congenital afibrinogenemia are
largely unknown, except for a recently reported 11-kb deletion of the
fibrinogen A -chain gene. Nevertheless, mutation mechanisms other
than the deletion of a fibrinogen gene are likely to exist because
patients with afibrinogenemia showing no gross alteration within the
fibrinogen cluster have been reported. We tested this hypothesis by
studying the affected members of two families, one Italian and one
Iranian, who had no evidence of large deletions in the fibrinogen
genes. Sequencing of the fibrinogen genes in the 2 probands detected 2 different homozygous missense mutations in exons 7 and 8 of the
B -chain gene, leading to amino acid substitutions Leu353Arg and
Gly400Asp, respectively. Transient transfection experiments with
plasmids expressing wild-type and mutant fibrinogens demonstrated that
the presence of either mutation was sufficient to abolish fibrinogen
secretion. These findings demonstrated that missense mutations in the
B fibrinogen gene could cause congenital afibrinogenemia by
impairing fibrinogen secretion.
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