Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study

• Published in: Human mutation 2005-03, Vol.25 (3), p.259-269
• Main Authors: Biguzzi, Eugenia, Razzari, Cristina, Lane, David A., Castaman, Giancarlo, Cappellari, Antonio, Bucciarelli, Paolo, Fontana, Gessica, Margaglione, Maurizio, D'Andrea, Giovanna, Simmonds, Rachel E., Rezende, Suely M., Preston, Roger, Prisco, Domenico, Faioni, Elena M.
• Format: Article
• Language: English
• Subjects: Codon, Nonsense; DNA Mutational Analysis; expression studies; Factor Va - analysis; Genetic Heterogeneity; Humans; Italy - epidemiology; Mutation, Missense; Proportional Hazards Models; PROS1; protein S; Protein S - genetics; Protein S Deficiency - complications; Protein S Deficiency - epidemiology; Protein S Deficiency - genetics; Pulmonary Embolism - epidemiology; Pulmonary Embolism - etiology; Risk Assessment; RNA Splice Sites - genetics; thrombophilia; Thrombophilia - etiology; Thrombophilia - genetics; Thrombophlebitis - epidemiology; Thrombophlebitis - etiology; thrombotic risk; Venous Thrombosis - epidemiology; Venous Thrombosis - etiology
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.20136

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. © 2005 Wiley‐Liss, Inc.