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A novel dysfunctional protein C (Protein C Padua 2) associated with a thrombotic tendency: substitution of Cys for Arg-1 results in a strongly reduced affinity for binding of Ca++

Girolami, A., Simioni, P., Girolami, B., Marchiori, A., Millar, David Stuart, Bignell, P., Kakkar, V. V. and Cooper, David Neil 1993. A novel dysfunctional protein C (Protein C Padua 2) associated with a thrombotic tendency: substitution of Cys for Arg-1 results in a strongly reduced affinity for binding of Ca++. British Journal of Haematology 85 (3) , pp. 521-527. 10.1111/j.1365-2141.1993.tb03342.x

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Abstract

A dysfunctional protein C (PC) molecule (Protein C Padua 2) was found in a 40-year-old man presenting with recurrent deep vein thrombosis/pulmonary embolism and a family history of thrombotic disease. The patient exhibited a normal PC antigen level, normal chromogenic activity (using Protac as PC activator) but markedly reduced coagulometric activity. After adsorption of patient plasma onto AI(OH), between 30% and 45% PC antigen/chromogenic activity but no coagulometric activity was detectable in the supernatant. The dysfunctional molecule exhibited reduced affinity for a Ca++ dependent anti-protein C monoclonal antibody as detected by specific ELISA assay. Immunoblotting experiments showed that PC Padua 2 had an increased MW (95 kD v 65 kD for normal PC). The lesion responsible was determined by PCR/direct sequencing to be a heterozygous CGT/TGT transition in exon 3 of the protein C gene resulting in the substitution of Arg by Cys at residue — 1 in the pro-peptide leader sequence. The presence of a high MW PC was consistent with the fact that (part of) the propeptide (at least Cys-1) still was attached to the protein C molecule. This finding could also explain the strongly reduced affinity of PC Padua 2 for the Ca++ dependent anti-protein C monoclonals.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley-Blackwell
ISSN: 0007-1048
Last Modified: 16 Apr 2019 20:52
URI: http://orca.cf.ac.uk/id/eprint/62009

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