Ile73Asn mutation in protein C introduces a new N-linked glycosylation site on the first EGF-domain of protein C and causes thrombosis

SummaryProteins that fail to attain their correct three-dimensional structure are retained in the endoplasmic reticulum (ER) and eventually degraded within the cells. We investigated the degradation of mutant proteins, using naturally occurring protein C (PC) mutants (Arg178Gln and Cys331Arg) which lead to congenital deficiencies. Chinese hamster ovary (CHO) cells were transfected with normal or mutant expression vectors. The introduction of mutation at Asn329 of an unusual sequence Asn-X-Cys for N-linked glycosylation revealed that the mutation at Cys331, which may preclude a formation of disulfide bond with Cys345, resulted in no addition of N-linked oligosaccharides at Asn329. PC mutants with 4 glycosylation sites were gradually glycosylated in the ER, and the fourth glycosylation site is less accessible for glycosylation as reported for PC in plasma.The half lives of PC178 and PC331 mutants were about 5 and 4 h, respectively. PC mutants were degraded, but the degradation was inhibited by inhibitors for proteasome. Mannose trimming of N-linked oligosaccharides after glucose removal targeted PC mutants for degradation by proteasomes. And also the inhibition of glucose trimming immediately led to mannose trimming, resulting in the accelerated degradation of PC mutants. These degradations were inhibited by mannosidase I inhibitor, kifunensine. These results indicate that the initiation of mannose trimming by mannosidase I leads to the proteasomemediated degradation of glucose-trimmed or untrimmed PC mutants.

Download Full-text

Activated protein C: the cure for sepsis - again?

Anaesthesia ◽

10.1046/j.1365-2044.2001.02441.x ◽

2001 ◽

Vol 56 (12) ◽

pp. 1133-1135 ◽

Cited By ~ 1

Author(s):

Tariq Hoth ◽

Timothy W. Evans

Keyword(s):

Protein C ◽

Activated Protein C

Download Full-text

Chromatographic purification and properties of a therapeutic human protein C concentrate

Journal of Chromatography B ◽

10.1016/s0021-9673(02)02002-2 ◽

2003 ◽

Author(s):

M Radosevich

Keyword(s):

Protein C ◽

Human Protein ◽

Chromatographic Purification ◽

Purification And Properties ◽

Protein C Concentrate

Download Full-text

Homozygous mutation in ABCA3 Lipid-Transporter defect (EXON 9) and low level of surfactant protein C

Klinische Pädiatrie ◽

10.1055/s-0030-1261412 ◽

2010 ◽

Vol 222 (S 01) ◽

Author(s):

J Pöschl ◽

P Ruef ◽

M Griese ◽

P Lohse ◽

C Aslanidis ◽

...

Keyword(s):

Protein C ◽

Surfactant Protein ◽

Homozygous Mutation ◽

Surfactant Protein C ◽

Low Level ◽

Exon 9 ◽

Lipid Transporter

Download Full-text

Coagulation Factor V Leiden Mutation Was Detected in the Patients with Activated Protein C Resistance in Thailand

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615201 ◽

1998 ◽

Vol 80 (08) ◽

pp. 344-345 ◽

Cited By ~ 2

Author(s):

Pasra Arnutti ◽

Motofumi Hiyoshi ◽

Wichai Prayoonwiwat ◽

Oytip Nathalang ◽

Chamaiporn Suwanasophon ◽

...

Keyword(s):

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Coagulation Factor ◽

Factor V ◽

Activated Protein C Resistance ◽

Factor V Leiden Mutation ◽

Coagulation Factor V

Download Full-text

Alveolar dynamics and beyond – The importance of surfactant protein C in cholesterol metabolism and lung homeostasis

10.1055/s-0037-1615322 ◽

2018 ◽

Author(s):

J Ruwisch ◽

N Roldan ◽

J Perez-Gil ◽

TE Weaver ◽

M Ochs ◽

...

Keyword(s):

Protein C ◽

Cholesterol Metabolism ◽

Surfactant Protein ◽

Surfactant Protein C

Download Full-text

High Levels of Circulating Thrombomodulin in Human Foetuses and Children

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614596 ◽

1999 ◽

Vol 81 (06) ◽

pp. 906-909 ◽

Cited By ~ 12

Author(s):

Marie-Hélène Aurousseau ◽

Danielle Gozin ◽

Fernand Daffos ◽

Armando D’Angelo ◽

François Forestier ◽

...

Keyword(s):

Cell Proliferation ◽

Endothelial Cell ◽

Protein C ◽

Endothelial Cell Surface ◽

A Value ◽

Median Level ◽

Group A ◽

Anticoagulant Function ◽

Cell Surface Proteoglycan ◽

Human Foetuses

SummaryThrombomodulin (TM) is an endothelial cell surface proteoglycan with anticoagulant functions, also implicated in cell proliferation, cell-cell adhesion and differentiation. In this study we determined circulating plasma TM (pTM) levels in human foetuses at different stages of pregnancy, at birth and in childhood. TM levels increased with gestational age, the median level reaching a peak of approximately 165 ng/ml between the 23rd and 26th week, thereafter decreasing gradually, reaching a value of 108 ng/ml at birth. pTM continues to decrease progressively during childhood, reaching in the 5-15 years group a median of 56 ng/ml which approaches the adult value. The pTM peak was statistically significant and represents a specific foetal phenomenon as it was independent of the corresponding maternal values. As a whole, the pTM pattern during foetal maturation appears totally different from that of protein C, prothrombin and other coagulation activators and inhibitors and thus, TM may play in the foetus another role in addition to its well-known anticoagulant function.

Download Full-text

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614518 ◽

1999 ◽

Vol 81 (04) ◽

pp. 527-531 ◽

Cited By ~ 114

Author(s):

U. Kjellberg ◽

N.-E. Andersson ◽

S. Rosén ◽

L. Tengborn ◽

M. Hellgren

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Protein C ◽

Activated Protein C ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Reference Level ◽

Soluble Fibrin ◽

Prothrombin Fragment ◽

D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

Download Full-text

Beckenvenenthrombose im 16. Lebensjahr bei angeborener Vena-cava-inferior-Atresie und Ecstasy-Abusus

Phlebologie ◽

10.1055/s-0037-1617356 ◽

2003 ◽

Vol 32 (02) ◽

pp. 50-53

Author(s):

C. Pieck ◽

P. Sander ◽

F. G. Bechara ◽

P. Altmeyer ◽

M. Stücker

Keyword(s):

Protein C ◽

Vena Cava ◽

Protein S ◽

Sich Eine ◽

Farbkodierte Duplexsonographie ◽

Vena Cava Inferior ◽

Vena Iliaca ◽

Vena Femoralis

ZusammenfassungKasuistik: Eine kaukasische Patientin, die sich wegen kosmetisch störender Varizen an der Bauchdecke und den Leisten vorstellte, erlitt mit 16 Jahren während einer exzessiven Tanzveranstaltung unter dem Einfluss von Ecstasy (3,4-Methylendioxymethamphetamin) aus kompletter Gesundheit bei damals asymptomatischer Vena-cava-inferior-Atresie eine akute Beckenvenenthrombose. Diagnostik: Bidirektionale Dopplersonographie, farbkodierte Duplexsonographie, Kernspintomographie mit Magnevist-Kontrastmittel der Venen beider Beine bzw. im Bereich des kleinen Beckens, Bestimmung der Serumkonzentration von Protein C und Protein S, Ausschluss von APC-Resistenz und Faktor-V-Leiden-Mutation. Ergebnisse: In der farbkodierten Duplexsonographie thrombosierte Vena iliaca externa sowie septierte, jedoch suffiziente Vena femoralis communis beidseits, keine Insuffizienzen oder Thromben in den übrigen extraund intrafaszialen Beinvenen nachweisbar. In der Kernspintomographie der Beckenvenen stellte sich eine Hypoplasie der Vena cava inferior oberhalb der Nierenetage und eine Atresie der Vena cava inferior unterhalb der Nierenetage dar sowie ein ausgeprägter venöser Kollateralkreislauf im Bereich des Beckens über die Vv. iliacae internae beidseits und die Vv. lumbales ascendentes beidseits bei varikös entarteten Kollateralvenen im Bereich der Bauchdecke beidseits mit Anschluss an die V. femoralis communis beidseits. Die untersuchten Gerinnungsparameter blieben unauffällig. Schlussfolgerung: Ecstasy-Abusus kann in Kombination mit starker körperlicher Anstrengung zu Exsikkose und Hämokonzetration führen. Dies sehen wir als letzte Ursache der Thrombose bei bestehender Vena-cava-Aplasie.

Download Full-text

Gerinnungsstörungen und Schlaganfall

Hämostaseologie ◽

10.1055/s-0037-1616976 ◽

2006 ◽

Vol 26 (04) ◽

pp. 309-315 ◽

Cited By ~ 1

Author(s):

Ch. C. Eschenfelder ◽

R. Stingele ◽

J. A. Zeller

Keyword(s):

Protein C ◽

Foramen Ovale ◽

Offenes Foramen Ovale ◽

At Iii

ZusammenfassungHereditäre und erworbene Gerinnungsstörungen können bei der Schlaganfallentstehung eine wichtige Rolle spielen. Wegen der Seltenheit der meisten erblichen Gerinnungsstörungen und der erheblichen Kosten, die sich aus einer unkritischen Indikationsstellung ergeben, ist eine maßgeschneiderte Diagnostik sinnvoll. Suggestive Hinweise auf eine Gerinnungsstörung sind niedriges Lebensalter, mehrfache Thrombosen in der Anamnese, altersuntypische Gefäßdegenerationen, vorherige Aborte bei Schlaganfallpatientinnen oder strukturelle Herzveränderungen (z. B. offenes Foramen ovale). Störungen von AT III, Protein C und S, APC-Resistenz, Prothrombinmutation, Homocysteinämie, Antiphospholipidantikörper und prokoagulatorische zelluläre Interaktionen werden diskuiert.

Download Full-text