Hereditary protein C deficiency caused by the Ala267Thr mutation in the protein C gene is associated with symptomatic and asymptomatic venous thrombosis

Tjeldhorn, Lena; Sandset, Per Morten; Haugbro, Kaia; Skretting, Grethe

doi:10.1016/j.thromres.2009.05.013

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…The level of secreted PC mutant was in agreement with the observed plasma PC protein level in our patient who had 12% of the normal level [29]. The differences in protein levels of the two PC variants were not due to reduced transcription of the mutated gene.…”

Section: Discussionsupporting

confidence: 89%

“…The present study provides evidence that the mechanism of PC deficiency caused by the A267T mutation [29] most likely involves impaired synthesis and also reduced secretion of the mutant. In contrast to what has been demonstrated for several other PC mutations causing PC deficiency [15,20,28], the effect of the present mutation on proteasomal degradation was minimal.…”

Section: Discussionmentioning

confidence: 76%

“…The aim of the present work was to characterize the A267T PC mutation previously reported in a patient with PC deficiency [29]. Using site-directed mutagenesis to generate A267T PC cDNA and subsequent transient transfections, we explored the potential molecular mechanism(s) by which this mutation may cause a reduction of the PC level in the plasma of the patient.…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport

et al. 2010

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BackgroundActivated protein C (PC) is a serine protease that regulates blood coagulation by inactivating coagulation factors Va and VIIIa. PC deficiency is an autosomally inherited disorder associated with a high risk of recurrent venous thrombosis. The aim of the study was to explore the mechanisms responsible for severe PC deficiency in a patient with the protein C A267T mutation by in-vitro expression studies.ResultsHuh7 and CHO-K1 cells were transiently transfected with expression vectors containing wild-type (WT PC) and mutated PC (A267T PC) cDNAs. PC mRNA levels were assessed by qRT-PCR and the PC protein levels were measured by ELISA. The mRNA levels of WT PC and A267T PC were similar, while the intracellular protein level of A267T PC was moderately decreased compared to WT PC. The secretion of A267T PC into the medium was severely impaired. No differences in molecular weights were observed between WT and A267T PC before and after treatment with endo-β-N-acetylglucosaminidase. Proteasomal and lysosomal degradations were examined using lactacystin and bafilomycin, respectively, and revealed that A267T PC was slightly more susceptible for proteasomal degradation than WT PC. Intracellular co-localization analysis indicated that A267T PC was mainly located in the endoplasmic reticulum (ER), whereas WT PC was observed in both ER and Golgi.ConclusionsIn contrast to what has been reported for other PC mutants, intracellular degradation of A267T PC was not the main/dominant mechanism underlying the reduced intracellular and secretion levels of PC. Our results indicate that the A267T mutation most likely caused misfolding of PC, which might lead to increased retention of the mutated PC in ER.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport

et al. 2010

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“…The important negative regulator of coagulation, thrombomodulin, binds thrombin to prevent it from cleaving fibrinogen or activating PAR-1. Thrombomodulin-thrombin complexes also activate the anticoagulant, protein C. Hereditary deficiency of protein C is an established risk factor for venous thrombosis [ 44 ], as activated protein C (APC) cleaves and inactivates the coagulants, FVa and factor VIIIa (FVIIIa). Plasminogen and plasminogen activator coreceptors that accelerate and localize plasmin formation to the cell surface, such as uPAR and the annexin A2 heterotetramer (AIIt) [ 28 ], are important regulators of fibrinolysis.…”

Section: Regulation Of Coagulation and Fibrinolysismentioning

confidence: 99%

The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease

Schuliga

2015

Mediators of Inflammation

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Aside from their role in hemostasis, coagulant and fibrinolytic proteases are important mediators of inflammation in diseases such as asthma, atherosclerosis, rheumatoid arthritis, and cancer. The blood circulating zymogens of these proteases enter damaged tissue as a consequence of vascular leak or rupture to become activated and contribute to extravascular coagulation or fibrinolysis. The coagulants, factor Xa (FXa), factor VIIa (FVIIa), tissue factor, and thrombin, also evoke cell-mediated actions on structural cells (e.g., fibroblasts and smooth muscle cells) or inflammatory cells (e.g., macrophages) via the proteolytic activation of protease-activated receptors (PARs). Plasmin, the principle enzymatic mediator of fibrinolysis, also forms toll-like receptor-4 (TLR-4) activating fibrin degradation products (FDPs) and can release latent-matrix bound growth factors such as transforming growth factor-β (TGF-β). Furthermore, the proteases that convert plasminogen into plasmin (e.g., urokinase plasminogen activator) evoke plasmin-independent proinflammatory actions involving coreceptor activation. Selectively targeting the receptor-mediated actions of hemostatic proteases is a strategy that may be used to treat inflammatory disease without the bleeding complications of conventional anticoagulant therapies. The mechanisms by which proteases of the coagulant and fibrinolytic systems contribute to extravascular inflammation in disease will be considered in this review.

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“…Putting the results of all epidemiological studies together, one can conclude that the risk of developing thrombosis among individuals with genetic defect in PROC or PROS1 varies considerably in the various studies that have been preformed. In addition to methodological variability, this could be due to gene-gene or gene-environment interactions, many of which have not yet been discovered (30,31).…”

Section: Protein C and S Deficiencies: Epidemiological Aspects And Clmentioning

confidence: 99%

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

Bereczky

Kovács

Muszbek

2010

Clinical Chemistry and Laboratory Medicine

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Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play an important role in the regulation of blood coagulation as natural anticoagulants. PC is activated by thrombin and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V. The free form of PS is an important cofactor of APC. Deficiencies in these proteins lead to an increased risk of venous thromboembolism; a few reports have also associated these deficiencies with arterial diseases. The degree of risk and the prevalence of PC and PS deficiency among patients with thrombosis and in those in the general population have been examined by several population studies with conflicting results, primarily due to methodological variability. The molecular genetic background of PC and PS deficiencies is heterogeneous. Most of the mutations cause type I deficiency (quantitative disorder). Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases. The diagnosis of PC and PS deficiencies is challenging; functional tests are influenced by several pre-analytical and analytical factors, and the diagnosis using molecular genetics also has special difficulties. Large gene segment deletions often remain undetected by DNA sequencing methods. The presence of the PS pseudogene makes genetic diagnosis even more complicated. Clin Chem Lab Med 2010;48:S53-66.

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Hereditary protein C deficiency caused by the Ala267Thr mutation in the protein C gene is associated with symptomatic and asymptomatic venous thrombosis

Cited by 8 publications

References 35 publications

Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport

Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport

The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

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