The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.

Hdl Handle:
http://hdl.handle.net/10147/207821
Title:
The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.
Authors:
Preston, Roger J S; Morse, Colin; Murden, Sherina L; Brady, Sara Kate; O'Donnell, James S; Mumford, Andrew D
Affiliation:
Haemostasis Research Group, Institute of Molecular Medicine, Trinity College, Dublin, St James Hospital, Dublin, Ireland.
Citation:
Br J Haematol. 2009 Mar;144(6):946-53. Epub 2008 Dec 26.
Journal:
British journal of haematology
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207821
DOI:
10.1111/j.1365-2141.2008.07550.x
PubMed ID:
19133979
Abstract:
We 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.
Language:
eng
MeSH:
Adolescent; Adult; Aged; *Amino Acid Substitution; Autoantigens/blood; Blood Coagulation/*genetics; Blood Coagulation Tests; Child; Female; Genotype; Humans; Male; Pedigree; Phenotype; Protein C/*genetics/immunology/metabolism; Protein C Deficiency/complications/*genetics/metabolism; Purpura Fulminans/genetics; Thrombin/biosynthesis; Thrombosis/etiology/genetics
ISSN:
1365-2141 (Electronic); 0007-1048 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorPreston, Roger J Sen_GB
dc.contributor.authorMorse, Colinen_GB
dc.contributor.authorMurden, Sherina Len_GB
dc.contributor.authorBrady, Sara Kateen_GB
dc.contributor.authorO'Donnell, James Sen_GB
dc.contributor.authorMumford, Andrew Den_GB
dc.date.accessioned2012-02-01T10:45:40Z-
dc.date.available2012-02-01T10:45:40Z-
dc.date.issued2012-02-01T10:45:40Z-
dc.identifier.citationBr J Haematol. 2009 Mar;144(6):946-53. Epub 2008 Dec 26.en_GB
dc.identifier.issn1365-2141 (Electronic)en_GB
dc.identifier.issn0007-1048 (Linking)en_GB
dc.identifier.pmid19133979en_GB
dc.identifier.doi10.1111/j.1365-2141.2008.07550.xen_GB
dc.identifier.urihttp://hdl.handle.net/10147/207821-
dc.description.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.en_GB
dc.language.isoengen_GB
dc.subject.meshAdolescenten_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.mesh*Amino Acid Substitutionen_GB
dc.subject.meshAutoantigens/blooden_GB
dc.subject.meshBlood Coagulation/*geneticsen_GB
dc.subject.meshBlood Coagulation Testsen_GB
dc.subject.meshChilden_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGenotypeen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMaleen_GB
dc.subject.meshPedigreeen_GB
dc.subject.meshPhenotypeen_GB
dc.subject.meshProtein C/*genetics/immunology/metabolismen_GB
dc.subject.meshProtein C Deficiency/complications/*genetics/metabolismen_GB
dc.subject.meshPurpura Fulminans/geneticsen_GB
dc.subject.meshThrombin/biosynthesisen_GB
dc.subject.meshThrombosis/etiology/geneticsen_GB
dc.titleThe protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.en_GB
dc.contributor.departmentHaemostasis Research Group, Institute of Molecular Medicine, Trinity College, Dublin, St James Hospital, Dublin, Ireland.en_GB
dc.identifier.journalBritish journal of haematologyen_GB
dc.description.provinceLeinster-
All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.