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Molecular pathogenesis of type I congenital plasminogen deficiency:
expression of recombinant human mutant plasminogens in mammalian cells
H Azuma, N Mima, M Shirakawa, K Miyamoto, H Yamaguchi, T Mitsui, T Shigekiyo and S Saito
First Department of Internal Medicine, School of Medicine, University of
Tokushima, Japan.
We previously reported the genetic abnormality in a Japanese family with
type I congenital plasminogen deficiency caused by a Ser572 to Pro572
mutation. To characterize the molecular pathogenesis of the disease in this
family, we expressed recombinant human wild-type and mutant (rS572P)
plasminogens in COS-1 cells. Activation-resistant wild- type and mutant
plasminogen stable transfectants in CHO-K1 cells also were established.
Transient transfection and metabolic labeling experiments followed by
immunoprecipitation analysis showed that the mutant plasminogen was
secreted from COS-1 cells in reduced amounts, compared with the wild type.
Endo H digestion of the wild-type and mutant plasminogen showed no shift in
their migrations on sodium dodecyl sulfate-polyacrylamide gel
electrophoresis analysis, indicating that both contain complex type
oligosaccharide structures and could therefore be secreted. Furthermore,
the secretion of activation- resistant mutant plasminogen was significantly
reduced. Pulse-chase experiments and Northern blot analysis showed that the
impaired secretion of the mutant plasminogen was the consequence of the
accumulation of the mutant protein inside the cells but not of reduced
plasminogen mRNA. Immunocytochemical staining of stable transfectants also
revealed that CHO-K1 cells expressing the activation-resistant mutant
plasminogen stained mainly in the perinuclear area, suggesting delayed
processing of the mutant protein in the intracellular transport pathway. We
conclude that the impaired secretion of mutant plasminogen, due to
intracellular accumulation, is the molecular pathogenesis of type I
congenital plasminogen deficiency caused by a Ser572 to Pro572 mutation.
Volume 89,
Issue 1,
pp. 183-190,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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