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.

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+.
AuthorsB Zöller, P García de Frutos, B Dahlbäck
JournalBlood (Blood) Vol. 85 Issue 12 Pg. 3524-31 (Jun 15 1995) ISSN: 0006-4971 [Print] UNITED STATES
PMID7780139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Complement Inactivator Proteins
  • Glycoproteins
  • Protein S
  • Complement C4b
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carrier Proteins (blood)
  • Child
  • Complement C4b (metabolism)
  • Complement Inactivator Proteins
  • Family
  • Female
  • Glycoproteins
  • Humans
  • Male
  • Middle Aged
  • Protein S (analysis)
  • Protein S Deficiency (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: