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Evaluation of the relationship between protein S and C4b-binding protein
isoforms in hereditary protein S deficiency demonstrating type I and type
III deficiencies to be phenotypic variants of the same genetic disease
B Zoller, P Garcia de Frutos and B Dahlback
Department of Clinical Chemistry, University of Lund, Malmo General
Hospital, Sweden.
Type III protein S deficiency is characterized by a low plasma level of
free protein S, whereas the total concentration of protein S is normal. In
contrast, both free and total protein S levels are low in type I
deficiency. To elucidate the molecular mechanism behind the selective
deficiency of free protein S in type III deficiency, the relationship
between the plasma concentrations of beta-chain containing isoforms of
C4b-binding protein (C4BP beta+) and different forms of protein S (free,
bound, and total) was evaluated in 327 members of 18 protein S- deficient
families. In normal relatives (n = 190), protein S correlated well with
C4BP beta+, with free protein S (96 +/- 23 nmol/L) being equal to the molar
excess of protein S (355 +/- 65 nmol/L) over C4BP beta+ (275 +/- 47
nmol/L). In protein S-deficient family members (n = 117), the equimolar
relationship between protein S (215 +/- 50 nmol/L) and C4BP beta+ (228 +/-
51 nmol/L), together with the high affinity of the interaction, resulted in
low levels of free protein S (16 +/- 10 nmol/L). Free protein S levels were
distinctly low in protein S- deficient members, whereas in 47 of the
protein S-deficient individuals, the concentration of total protein S was
within the normal range, which fulfils the criteria for type III
deficiency. The remaining 70 had low levels of both total and free protein
S and, accordingly, would be type I deficient. Coexistence of type I and
type III deficiency was found in 14 families, suggesting the two types of
protein S deficiency to be phenotypic variants of the same genetic disease.
Interestingly, not only protein S but also C4BP beta+ levels were decreased
in orally anticoagulated controls and even more so in anticoagulated
protein S-deficient members, suggesting that the concentration of C4BP
beta+ is influenced by that of protein S. In conclusion, our results
indicate that type I and type III deficiencies are phenotypic variants of
the same genetic disease and that the low plasma concentrations of free
protein S in both types are the result of an equimolar relationship between
protein S and C4BP beta+.
Volume 85,
Issue 12,
pp. 3524-3531,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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