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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-03-0909.
Submitted March 22, 2002
Accepted May 31, 2002
Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency
Suely M Rezende, David A Lane, Blandine Mille-Baker, Michel M Samama, Jaqueline Conard, and Rachel E Simmonds*
Haematology Department, Division of Investigative Science, Imperial College of Science, Technology and Medicine, London, United Kingdom
Service d'Hematologie Biologique, Hotel-Dieu, Paris, France
* Corresponding author; email: r.simmonds{at}ic.ac.uk.
We have identified two PROS1 missense mutations in the exon that encodes the vitamin K-dependent Gla-domain of protein S (Gly11Asp and Thr37Met) in a kindred with phenotypic protein S deficiency and thrombosis. In studies utilising recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor Va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (p<0.001), and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (p<0.001) and decreased affinity for an antibody specific for the Ca2+-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only modestly (1.5-fold, p<0.001) reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterisation of natural protein S Gla domain variants highlights the importance of the high affinity protein S-phospholipid interaction for its anticoagulant role.
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