Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk) |
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Authors: | Lefebvre Phil Velasco Pauline T Dear Amy Lounes Karim C Lord Susan T Brennan Stephen O Green David Lorand Laszlo |
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Institution: | Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. |
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Abstract: | Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of crosslinked gamma-gamma fibrin chain dimers without high polymers of alpha n. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aalpha-chain residues 241-476 but not by antibodies to Aalpha219-348 or Aalpha349-406. DNA analysis revealed a heterozygous CAA-->TAA mutation at the codon for amino acid 328 of the Aalpha gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aalpha chain. Analysis of purified fibrinogen revealed expression of the abnormal Aalpha chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aalpha mutation, a GT-->TT splice site mutation in intron 4 (IVS4 + 1 G> T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms. |
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