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Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study
Author(s) -
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.
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20136
Subject(s) - missense mutation , biology , pulmonary embolism , proband , hazard ratio , gastroenterology , medicine , thrombosis , deep vein , thrombophilia , venous thrombosis , protein c , genetics , gene , phenotype , mutation , confidence interval
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.