[PROC_HUMAN] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare.
[PROC_HUMAN] Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.
The structure of the Gla-domainless form of the human anticoagulant enzyme activated protein C has been solved at 2.8 A resolution. The light chain is composed of two domains: an epidermal growth factor (EGF)-like domain modified by a large insert containing an additional disulfide, followed by a typical EGF-like domain. The arrangement of the long axis of these domains describes an angle of approximately 80 degrees. Disulfide linked to the light chain is the catalytic domain, which is generally trypsin-like but contains a large insertion loop at the edge of the active site, a third helical segment, a prominent cationic patch analogous to the anion binding exosite I of thrombin and a trypsin-like Ca[II] binding site. The arrangement of loops around the active site partially restricts access to the cleft. The S2 and S4 subsites are much more polar than in factor Xa and thrombin, and the S2 site is unrestricted. While quite open and exposed, the active site contains a prominent groove, the surface of which is very polar with evidence for binding sites on the primed side, in addition to those typical of the trypsin class found on the non-primed side.
The 2.8 A crystal structure of Gla-domainless activated protein C.,Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, Bode W EMBO J. 1996 Dec 16;15(24):6822-31. PMID:9003757
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Miyata T, Zheng YZ, Sakata T, Kato H. Protein C Osaka 10 with aberrant propeptide processing: loss of anticoagulant activity due to an amino acid substitution in the protein C precursor. Thromb Haemost. 1995 Oct;74(4):1003-8. PMID:8560401
↑ Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C, et al.. Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci U S A. 1987 May;84(9):2829-32. PMID:2437584
↑ Grundy C, Chitolie A, Talbot S, Bevan D, Kakkar V, Cooper DN. Protein C London 1: recurrent mutation at Arg 169 (CGG----TGG) in the protein C gene causing thrombosis. Nucleic Acids Res. 1989 Dec 25;17(24):10513. PMID:2602169
↑ Reitsma PH, Poort SR, Allaart CF, Briet E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood. 1991 Aug 15;78(4):890-4. PMID:1868249
↑ Bovill EG, Tomczak JA, Grant B, Bhushan F, Pillemer E, Rainville IR, Long GL. Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood. 1992 Mar 15;79(6):1456-65. PMID:1347706
↑ Grundy CB, Schulman S, Tengborn L, Kakkar VV, Cooper DN. Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis. Hum Genet. 1992 Aug;89(6):685-6. PMID:1511989
↑ Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Heilman M, Toulon P, Fiessinger JN, Goossens M. Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. Hum Mutat. 1992;1(6):491-500. PMID:1301959 doi:http://dx.doi.org/10.1002/humu.1380010607
↑ Millar DS, Grundy CB, Bignell P, Moffat EH, Martin R, Kakkar VV, Cooper DN. A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing type 2 protein C deficiency and recurrent venous thrombosis. Blood Coagul Fibrinolysis. 1993 Apr;4(2):345-7. PMID:8499568
↑ Tsay W, Greengard JS, Montgomery RR, McPherson RA, Fucci JC, Koerper MA, Coughlin J, Griffin JH. Genetic mutations in ten unrelated American patients with symptomatic type 1 protein C deficiency. Blood Coagul Fibrinolysis. 1993 Oct;4(5):791-6. PMID:8292730
↑ Marchetti G, Patracchini P, Gemmati D, Castaman G, Rodeghiero F, Wacey A, Cooper DN, Tuddenham EG, Bernardi F. Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket. Br J Haematol. 1993 Jun;84(2):285-9. PMID:8398832
↑ Zheng YZ, Sakata T, Matsusue T, Umeyama H, Kato H, Miyata T. Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling. Blood Coagul Fibrinolysis. 1994 Oct;5(5):687-96. PMID:7865674
↑ Lind B, Schwartz M, Thorsen S. Six different point mutations in seven Danish families with symptomatic protein C deficiency. Thromb Haemost. 1995 Feb;73(2):186-93. PMID:7792728
↑ Couture P, Demers C, Morissette J, Delage R, Jomphe M, Couture L, Simard J. Type I protein C deficiency in French Canadians: evidence of a founder effect and association of specific protein C gene mutations with plasma protein C levels. Thromb Haemost. 1998 Oct;80(4):551-6. PMID:9798967
↑ Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, Bode W. The 2.8 A crystal structure of Gla-domainless activated protein C. EMBO J. 1996 Dec 16;15(24):6822-31. PMID:9003757