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Blood, 1 October 2000, Vol. 96, No. 7, pp. 2501-2505
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene
causing afibrinogenemia due to abnormal RNA splicing
Maurizio Margaglione,
Rosa Santacroce,
Donatella Colaizzo,
Davide Seripa,
Gennaro Vecchione,
Maria
Rosaria Lupone,
Domenico De
Lucia,
Paolo Fortina,
Elvira Grandone,
Corrado Perricone, and
Giovanni Di
Minno
From the Unità di Aterosclerosi e Trombosi, IRCCS
"Casa Sollievo della Sofferenza," S Giovanni Rotondo; Centro
Regionale per le Emocoagulopatie, Azienda Ospedaliera
"Santobono-Pausillipon," Istituto di Patologia Generale e
Oncologia, Seconda Università di Napoli, Napoli; Istituto di
Medicina Interna e Geriatria, Università di Palermo, Italy; and
Department of Pediatrics, University of Pennsylvania School of
Medicine, and the Children's Hospital of Philadelphia, PA.
Congenital afibrinogenemia is a rare autosomal recessive disorder
characterized by a hemorrhagic diathesis of variable severity. Although
more than 100 families with this disorder have been described, genetic
defects have been characterized in few cases. An investigation of a
young propositus, offspring of a consanguineous marriage, with
undetectable levels of functional and quantitative fibrinogen, was
conducted. Sequence analysis of the fibrinogen genes showed a
homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the
third intervening sequence (IVS) of the  -chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the
disappearance of a donor splice site. After transfection with a
construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), consistent with skipping of exon 3, but not the expected mRNA.
Sequencing of the abnormal mRNA showed the complete absence of exon 3. Skipping of exon 3 predicts the deletion of amino acid sequence from
residue 16 to residue 75 and shifting of reading frame at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the
truncated -chain gene product would not interact with other chains
to form the mature fibrinogen molecule. The current findings show that
mutations within highly conserved IVS regions of fibrinogen genes could
affect the efficiency of normal splicing, giving rise to congenital afibrinogenemia.
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