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A new substitution, gamma 358 Ser-->Cys, in fibrinogen Milano VII causes
defective fibrin polymerization
C Steinmann, C Bogli, M Jungo, B Lammle, G Heinemann, B Wermuth, R Redaelli, F Baudo and M Furlan
Central Hematology Laboratory, Inselspital, Bern, Switzerland.
Fibrinogen Milano VII is a hereditary fibrinogen variant detected in a
woman with no clinical symptoms of bleeding or thrombosis. Thrombin and
reptilase clotting times were prolonged in six family members from three
generations. Release of fibrinopeptides A and B was normal. Fibrin
polymerization was strongly delayed both in the presence and in the absence
of calcium. The structural defect was determined by sequence analysis of a
290-bp fragment of genomic DNA amplified by polymerase chain reaction and
cloned in M13mp19. The triplet TCT coding for the amino acid residue gamma
358 was found to be replaced by TGT, resulting in the substitution gamma
358 Ser-->Cys. Immunoblot analysis demonstrated the presence of
covalently linked fibrinogen albumin and fibrinogen (albumin)2 complexes.
Albumin was released from fibrinogen Milano VII by limited reduction with
2-mercaptoethanol. Fibrin polymerization was not normalized after removal
of albumin from fibrinogen Milano VII, suggesting that the delayed clot
formation is not due to steric hindrance caused by bound albumin but by
substitution of gamma 358 Ser by Cys itself. Our results indicate that the
residue gamma 358 Ser is essential for normal expression of the carboxy
terminal polymerization site on the fibrinogen gamma-chain.
Volume 84,
Issue 6,
pp. 1874-1880,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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