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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-03-0909.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2812-2819
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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,
Jacqueline Conard, and
Rachel E. Simmonds
From the Department of Haematology, Division of
Investigative Science, Hammersmith Campus, Imperial College of Science,
Technology, and Medicine, London, United Kingdom; and Service
d'Hématologie Biologique, Hôtel-Dieu, Paris,
France.
We have identified 2 PROS1 missense mutations in the
exon that encodes the vitamin K-dependent Gla domain of protein S
(Gly11Asp and Thr37Met) in kindred with phenotypic protein S deficiency and thrombosis. In studies using 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 < .001) and activity by 3.6-fold. The Gly11Asp
variant had 5.4-fold reduced affinity for anionic phospholipid vesicles
(P < .0001) 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 a modest 1.5-fold (P < .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 characterization 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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