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284 Gly
Arg Mutation
From the Molecular Pathology Laboratory,*
Christchurch
Hospital, Christchurch, New Zealand; and the 1st Servizio di Anatomia
Patologica,
Spedali Civili di Brescia,
Brescia, Italy
The proposita suffered from liver cirrhosis and biopsy
showed type 1 membrane-bound fiberglass inclusions. The hepatic
inclusion bodies were weakly periodic acid-Schiff
diastase-positive, and on immunoperoxidase staining reacted
specifically with anti-fibrinogen antisera. Coagulation investigations
revealed low functional and antigenic fibrinogen together with a
prolonged thrombin time of 37 seconds (normal, 17 to 22
seconds) suggestive of a hypodysfibrinogenemia. DNA sequencing of all
three fibrinogen genes showed a single heterozygous mutation of
GGG (Gly)
CGG (Arg) at codon 284 of the 
-chain gene.
However, examination of purified fibrinogen chains by sodium
dodecyl sulfate-polyacrylamide gel electrophoresis,
reverse-phase high-performance liquid chromatography,
ion-exchange high-performance liquid chromatography, and
isoelectric focusing, failed to show any evidence of the mutant
Br chain in plasma fibrinogen. This finding was
substantiated by electrospray ionization mass spectrometry,
which showed only a normal (and Bß) chain mass, but a
large increase in the portion of their disialo isoforms. We speculate
that misfolding of the variant protein causes hepatic retention and the
subsequent hypofibrinogenemia, and that the functional defect
(dysfibrinogenemia) results from hypersialylation of otherwise normal
Bß and chains consequent to the liver cirrhosis. These
conclusions were supported by studies on six other family members with
hypofibrinogenemia, and essentially normal clotting
times, who were heterozygous for the 284 GlyArg
mutation.
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