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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

Zöller, Bengt LU ; Garcia de Frutos, P. LU and Dahlbäck, Björn LU (1995) In Blood 85(12). p.3524-3531
Abstract
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 β-chain containing isoforms of C4b-binding protein (C4BPβ+) 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 C4BPβ+ with free protein S (96 ± 23 nmol/L) being equal to the molar excess of protein S (355 ± 65 nmol/L) over... (More)
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 β-chain containing isoforms of C4b-binding protein (C4BPβ+) 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 C4BPβ+ with free protein S (96 ± 23 nmol/L) being equal to the molar excess of protein S (355 ± 65 nmol/L) over C4BPβ+ (275 ± 47 nmol/L). In protein S-deficient family members (n = 117), the equimolar relationship between protein S (215 ± 50 nmol/L) and C4BPβ+ (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 proteinS-deficient members, whereas in 47 of the protein S-deficient individuals, the concentration of total protein S was within the normal range, which fulfills 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 C4BPβ+ levels were decreased in orally anticoagulated controls and even more so in anticoagulated protein S- deficient members, suggesting that the concentration of C4BPβ+ 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 C4BPβ+. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
keywords
CD4 antigen, protein S, warfarin, adolescent, adult, aged, anticoagulation, article, binding affinity, child, clinical article, controlled study, female, genetic risk, human, human cell, human tissue, male, phenotype, priority journal, protein binding, protein blood level, protein defect, protein deficiency, protein S deficiency
in
Blood
volume
85
issue
12
pages
8 pages
publisher
American Society of Hematology
external identifiers
  • scopus:0029017118
ISSN
0006-4971
language
English
LU publication?
yes
id
47893182-6508-49f9-a59c-431367abd97f
date added to LUP
2017-10-19 16:29:10
date last changed
2017-11-06 15:16:17
@article{47893182-6508-49f9-a59c-431367abd97f,
  abstract     = {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 β-chain containing isoforms of C4b-binding protein (C4BPβ+) 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 C4BPβ+ with free protein S (96 ± 23 nmol/L) being equal to the molar excess of protein S (355 ± 65 nmol/L) over C4BPβ+ (275 ± 47 nmol/L). In protein S-deficient family members (n = 117), the equimolar relationship between protein S (215 ± 50 nmol/L) and C4BPβ+ (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 proteinS-deficient members, whereas in 47 of the protein S-deficient individuals, the concentration of total protein S was within the normal range, which fulfills 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 C4BPβ+ levels were decreased in orally anticoagulated controls and even more so in anticoagulated protein S- deficient members, suggesting that the concentration of C4BPβ+ 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 C4BPβ+.},
  author       = {Zöller, Bengt and Garcia de Frutos, P. and Dahlbäck, Björn},
  issn         = {0006-4971},
  keyword      = {CD4 antigen,protein S,warfarin,adolescent,adult,aged,anticoagulation,article,binding affinity,child,clinical article,controlled study,female,genetic risk,human,human cell,human tissue,male,phenotype,priority journal,protein binding,protein blood level,protein defect,protein deficiency,protein S deficiency},
  language     = {eng},
  month        = {11},
  number       = {12},
  pages        = {3524--3531},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {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},
  volume       = {85},
  year         = {1995},
}