The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.
AuthorsPreston, Roger J S
Murden, Sherina L
Brady, Sara Kate
O'Donnell, James S
Mumford, Andrew D
AffiliationHaemostasis Research Group, Institute of Molecular Medicine, Trinity College, Dublin, St James Hospital, Dublin, Ireland.
*Amino Acid Substitution
Blood Coagulation Tests
Protein C Deficiency/complications/*genetics/metabolism
MetadataShow full item record
CitationBr J Haematol. 2009 Mar;144(6):946-53. Epub 2008 Dec 26.
JournalBritish journal of haematology
AbstractWe report a kindred with heritable protein C (PC) deficiency in which two siblings with severe thrombosis showed a composite type I and IIb PC deficiency phenotype, identified using commercial PC assays (proband: PC antigen 42 u/dl, amidolytic activity 40 u/dl, anticoagulant activity 9 u/dl). The independent PROC nucleotide variations c.669C>A (predictive of Ser181Arg) and c.131C>T (predictive of Asn2Ile) segregated with the type I and type IIb PC deficiency phenotypes respectively, but co-segregated in the siblings with severe thrombosis. Soluble thrombomodulin (sTM)-mediated inhibition of plasma thrombin generation from an individual with PC-Asn2Ile was lower (endogenous thrombin potential (ETP) 56 +/- 1% that of ETP determined without sTM) than control plasma (ETP 15 +/- 2%) indicating reduced PC anticoagulant activity. Recombinant APC-Asn2Ile exhibited normal amidolytic activity but impaired anticoagulant activity. Protein S (PS)-dependent anticoagulant activity of recombinant APC-Asn2Ile and binding of recombinant APC-Asn2Ile to endothelial protein C receptor (EPCR) were reduced compared to recombinant wild-type APC. Asn2 lies within the omega-loop of the PC/APC Gla domain and this region is critical for calcium-induced folding and subsequent interactions with anionic phospholipids, EPCR and PS. The disruption of these interactions in this naturally-occurring PC variant highlights their collective importance in mediating APC anticoagulant activity in vivo.
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