Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study
- 23 February 2005
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 25 (3), 259-269
- https://doi.org/10.1002/humu.20136
Abstract
The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in'vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (>75%) for three variants, which were considered neutral. Seven missense and five nonsense variants showed low (≤11%) expression levels and were classified as severe defects. Intermediate expression was observed for eight variants, which were evaluated by factor Va inactivation assay in order to be globally classified as severe or intermediate. Based on the cumulative data, the hazard ratio associated with causative variants was 4.9 (95% CI: 1.4–17.7) for deep vein thrombosis and/or pulmonary embolism, 5.1 (95% CI: 1.1–23.9) for superficial thrombophlebitis, and 4.8 (95% CI: 1.8–13.0) for any venous thrombosis. The hazard ratio for deep vein thrombosis and/or pulmonary embolism in carriers of severe defects only was 7.4 (95% CI: 1.6–24.1). PROSIT showed that dysfunctional variants causing PS deficiency are more common than expected and confirmed that PS deficiency is associated with increased thrombotic risk, although risk assessment is complicated by molecular heterogeneity. Hum Mutat 25:259–269, 2005.Keywords
This publication has 49 references indexed in Scilit:
- A Quantitative Trait Locus Influencing Free Plasma Protein S Levels on Human Chromosome 1qArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Deficient APC-cofactor activity of protein S Heerlen in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factorsBlood, 2000
- Protein S secretion differences of missense mutants account for phenotypic heterogeneityBlood, 2000
- Protein S Thr103Asn Mutation Associated with Type II Deficiency Reproduced In Vitro and Functionally CharacterisedThrombosis and Haemostasis, 2000
- Protein S Deficiency: A Database of Mutations – Summary of the First UpdateThrombosis and Haemostasis, 2000
- Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiencyHuman Mutation, 1999
- The protein C anticoagulant system: Inherited defects as basis for venous thrombosisThrombosis Research, 1995
- Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460Blood, 1990
- Familial protein S deficiency is associated with recurrent thrombosis.JCI Insight, 1984
- High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein.Proceedings of the National Academy of Sciences of the United States of America, 1981