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Thromb Haemost 1997; 78(01): 344-350
DOI: 10.1055/s-0038-1657550
Molecular basis of inherited thrombophilia: from genedefects to disease
Schattauer GmbH Stuttgart

Protein C Deficiency: from Gene Defects to Disease

Pieter H Reitsma
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Publication History

Publication Date:
12 July 2018 (online)

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  • References

  • 1 Walker FJ, Fay PJ. Regulation of blood coagulation by the protein C system. FASEB J 1992; 6: 2561-2567
    CrossrefPubMedGoogle Scholar
  • 2 Dahlbä B, Stenflo J. A natural anticoagulant pathway: proteins C, S, C4b-binding protein and thrombomodulin. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. eds. Haemostasis and Thrombosis. Edinburgh; Chuchill Livingstone: 1994: 671-698
    Google Scholar
  • 3 Esmon CT, Schwarz HP. An update on clinical and basic aspects of the protein C anticoagulant pathway. Trends Cardiovasc Med 1995; 5: 141-148
    CrossrefPubMedGoogle Scholar
  • 4 Poort SR, Michiels JJ, Reitsma PH, Bertina RM. Homozygosity for a novel missense mutation in the prothrombin gene causing a severe bleeding disorder. Thromb Haemost 1994; 72: 819-824
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Miyata T, Zheng Y-Z, Kato A, Kato H. A point mutation (Arg271→Cys) of a homozygote for dysfunctional prothrombin, prothrombin Obihiro, which has a region of high sequence variability. Br J Haematol 1995; 90: 688-692
    CrossrefPubMedGoogle Scholar
  • 6 Bezeaud A, Miyata T, Helley D, Zeng YZ, Kato H, Aillaud MF, Juhan-Vague I, Guillin MC. Functional consequences of the Ser334—>Pro mutation in a human factor X variant (factor XMarseille). European Journal of Biochemistry 1995; 234: 140-147
    CrossrefPubMedGoogle Scholar
  • 7 Marchetti G, Castaman G, Pinotti M, Lunghi B, Di IasioMG, Ruggieri M, Rodeghiero F, Bernardi F. Molecular bases of CRM+ factor X deficiency: A frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glul02Lys) in the second EGF-like domain. Br J Haematol 1995; 90: 910-915
    CrossrefPubMedGoogle Scholar
  • 8 Kim DJ, Thompson AR, Nash DR, James HL. Factors XWenalchee I and II: Compound heterozygosity involving two variant proteins. Biochim Biophys Acta Mol Basis Dis 1995; 1271: 327-334
    CrossrefPubMedGoogle Scholar
  • 9 Kim DJ, Thompson AR, James HL. Factor XKetchikan: A variant molecule in which Gly replaces a Gla residue at position 14 in the light chain. Hum Genet 1995; 95: 212-214
    PubMedGoogle Scholar
  • 10 Zheng DQ, Shurafa M, James HL. Factor VII G331D: a variant molecule involving replacement of a residue in the substrate-binding region of the catalytic domain. Blood Coagul Fibrinolysis 1996; 7: 93-96
    CrossrefPubMedGoogle Scholar
  • 11 Arbini AA, Mannucci M, Bauer KA. AThr359Met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule. Blood 1996; 87: 5085-5094
    PubMedGoogle Scholar
  • 12 Bernardi F, Castaman G, Pinotti M, Ferraresi P, Diiasio MG, Lunghi B, Rodeghiero F, Marchetti G. Mutation pattern in clinically asymptomatic coagulation factor VII deficiency. Hum Mut 1996; 8: 108-115
    CrossrefPubMedGoogle Scholar
  • 13 Giannelli F, Green PM, Sommer SS. et al. Haemophilia B (sixth edition): a database of point mutations and short additions and deletions. Nucleic Acids Res 1996; 24: 103-118
    CrossrefPubMedGoogle Scholar
  • 14 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper DN. Protein C deficiency: A database of mutations, 1995 update. Thromb Haemost 1995; 73: 876-889
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Borgel D, Duchemin J, Alhencgelas M, Matheron C, Aiach M, Gandrille S. Molecular basis for protein S hereditary deficiency - genetic defects observed in 118 patients with type I and type Ha deficiencies. J Lab Clin Med 1996; 128: 218-227
    CrossrefPubMedGoogle Scholar
  • 16 Foster D, Davie EW. Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci USA 1984; 81: 4766-4770
    CrossrefPubMedGoogle Scholar
  • 17 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985; 82: 4673-4677
    CrossrefPubMedGoogle Scholar
  • 18 Plutzky J, Hoskins JA, Long GL, Crabtree GR. Evolution and organization of the human protein C gene. Proc Natl Acad Sci USA 1986; 83: 546-550
    CrossrefPubMedGoogle Scholar
  • 19 Patracchini P, Aiello V, Palazzi P, Calzolari E, Bernardi F. Sublocalization of the human protein C gene on chromosome 2ql3-ql4. Hum Genet 1989; 81: 191-192
    CrossrefPubMedGoogle Scholar
  • 20 Foster DC, Rudinski MS, Schach BG, Berkner KL, Kumar AA, Hagen FS, Sprecher CA, Insley MY, Davie EW. Propeptide of human protein C is necessary for gamma-carboxylation. Biochemistry 1987; 26: 7003-7011
    CrossrefPubMedGoogle Scholar
  • 21 Wojcik EGC, Simioni P, Berg MVD, Girolami A, Bertina RM. Mutations which introduce free cysteine residues in the Gla-domain of vitamin K-dependent proteins result in the formation of complexes with alpha(l)-microglobulin. Thromb Haemost 1996; 75: 70-75
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Girolami A, Simioni P, Girolami B, Marchiori A, Millar DS, Bignell P, Kakkar VV, Cooper DN. A novel dysfunctional protein C (protein C Padua 2) associated with a thrombotic tendency: substitution of Cys for Arg-1 results in a strongly reduced affinity for binding of Ca++ . Br J Haematol 1993; 85: 521-527
    PubMedGoogle Scholar
  • 23 Diuguid DL, Rabiet MJ, Furie BC, Liebman HA, Furie B. Molecular basis of hemophilia B: a defective enzyme due to an unprocessed propeptide is caused by a point mutation in the factor IX precursor. Proc Natl Acad Sci USA 1986; 83: 5803-5807
    CrossrefPubMedGoogle Scholar
  • 24 Erdjument H, Lane DA, Ireland H, Panico M, Di MarzoV, Blench I, Morris HR. Formation of a covalent disulfide-linked antithrombin-albumin complex by an antithrombin variant, antithrombin “Northwick Park”. J Biol Chem 1987; 262: 13381-13384
    PubMedGoogle Scholar
  • 25 Greengard JS, Griffin JH, Fisher CL. Possible structural implications of 20 mutations in the protein C protease domain. Thro mb Haemostas 1994; 72: 869-873
    PubMedGoogle Scholar
  • 26 Wacey AI, Pemberton S, Cooper DN, Kakkar VV, Tuddenham EGD. A molecular model of the serine protease domain of activated protein C: application to the study of missense mutations causing protein C deficiency. Br J Haematol 1993; 84: 290-300
    CrossrefPubMedGoogle Scholar
  • 27 Greengard JS, Fisher CL, Villoutreix B, Griffin JH. Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: patterns revealed by three-dimensional molecular modelling of mutations of the protease domain. Proteins 1994; 18: 367-380
    CrossrefPubMedGoogle Scholar
  • 28 Hallam PJ, Wacey AI, Mannucci PM, Legnani C, Kuhnau W, Krawczak M, Kakkar VV, Cooper DN. A novel missense mutation (Thrl76→Ile) at the putative hinge of the → N-terminus of activated protein C. Hum Genet 1995; 95: 447-450
    PubMedGoogle Scholar
  • 29 Millar DS, Wacey AI, Voke J, Kakkar VV, Cooper DN. A novel point mutation (Val 297→Met) in the serine proteinase domain of protein C in a patient with both venous and arterial thromboembolic disease. Blood Coagul Fibrinolysis 1993; 4: 631-633
    CrossrefPubMedGoogle Scholar
  • 30 Katsumi A, Senda T, Yamashita Y, Yamazaki T, Hamaguchi M, Kojima T, Kobayashi S, Saito H. Protein C Nagoya, an elongated mutant of protein C, is retained within the endoplasmic reticulum and is associated with GRP78 and GRP94. Blood 1996; 87: 4164-4175
    PubMedGoogle Scholar
  • 31 Simioni P, Kalafatis M, Millar DS, Henderson SC, Luni S, Cooper DN, Girolami A. Compound heterozygous protein C deficiency resulting in the presence of only the beta-form of protein C in plasma. Blood 1996; 88: 2101-2108
    CrossrefPubMedGoogle Scholar
  • 32 Spek CA, Greengard JS, Griffin JH, Bertina RM, Reitsma PH. Two mutations in the promoter region of the human protein C gene both cause type I protein C deficiency by disruption of two HNF-3 binding sites. J Biol Chem 1995; 270: 24216-24221
    CrossrefPubMedGoogle Scholar
  • 33 Miao CH, Ho WT, Greenberg DL, Davie EW. Transcriptional regulation of the gene coding for human protein C. J Biol Chem 1996; 271: 9587-9594
    CrossrefPubMedGoogle Scholar
  • 34 Berg L, White DA, Alhaq A, Kakkar VV, Cooper DN. Disruption of a binding site for hepatocyte nuclear factor 1 (HNF-1) in the protein C (PROC) gene promoter is associated with hereditary thrombophilia. Hum Mol Genet 1994; 03: 2147-2152
    CrossrefPubMedGoogle Scholar
  • 35 Tsay W, Lee YM, Lee SC, Shen MC, Chen PJ. Characterization of human protein C gene promoter - insights from natural human mutants. DNA Cell Biol 1996; 15: 907-919
    CrossrefPubMedGoogle Scholar
  • 36 Krawczak M, Cooper DN. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 1991; 86: 425-441
    PubMedGoogle Scholar
  • 37 Soria JM, Morell M, Nicolau I, Estivill X, Sala N. Homozygosity for R87H missense mutation and for a rare intron 7 DNA variant (7054G→ A) in the PROC genes of three siblings initially classified as heterozygotes for protein C deficiency. Blood Coagul Fibrinolysis 1996; 07: 15-23
    CrossrefPubMedGoogle Scholar
  • 38 Soria JM, Berg LP, Fontcuberta J, Kakkar VV, Estivill X, Cooper DN, Sala N. Ectopic transcript analysis indicates that allelic exclusion is an important cause of type I protein C deficiency in patients with nonsense and frameshift mutations in the PROC gene. Thromb Haemostas 1996; 75: 870-876
    PubMedGoogle Scholar
  • 39 Berg LP, Soria JM, Formstone CJ, Morell M, Kakkar VV, Estivill X, Sala N, Cooper DN. Aberrant rna splicing of the protein C and protein S genes in healthy individuals. Blood Coagul Fibrinolysis 1996; 7: 625-631
    CrossrefPubMedGoogle Scholar
  • 40 Wehinger H, Geiger E, Freudenberg V, Schurmann J, Alexandrakis E, Witt I. Severe hereditary protein C deficiency in a newborn infant with fulminant purpura-successful treatment with phenprocoumon. Klin Padiatr 1985; 197: 116-120
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Rosenberg RD. The absence of the blood clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Thromb Haemost 1995; 74: 52-57
    PubMedGoogle Scholar
  • 42 Reitsma PH, Poort SR, Allaart CF, Briët 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; 78: 890-894
    PubMedGoogle Scholar
  • 43 Matsuda M, Sugo T, Sakata Y, Murayama H, Mimuro J, Tanabe S, Yoshitake S. A thrombotic state due to an abnormal protein C. N Engl J Med 1988; 319: 1265-1268
    CrossrefPubMedGoogle Scholar
  • 44 Grundy CB, 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; 17: 10513
    CrossrefPubMedGoogle Scholar
  • 45 Grundy CB, Schulman S, Krawczak M, Kobosko J, Kakkar VV, Cooper DN. Protein C deficiency and thromboembolism: Recurrent mutation at Arg 306 in the protein C gene. Hum Genet 1992; 88: 586-588
    CrossrefPubMedGoogle Scholar
  • 46 Cooper DN, Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet 1988; 78: 151-155
    CrossrefPubMedGoogle Scholar
  • 47 Krawczak M, Reitsma PH, Cooper DN. The mutational demography of protein C deficiency. Hum Genet 1995; 96: 142-146
    CrossrefPubMedGoogle Scholar
  • 48 Reitsma PH, Poort SR, Bernardi F, Gandrille S, Long GL, Sala N, Cooper DN. Protein C deficiency: a database of mutations. Thromb Haemost 1993; 69: 77-84
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Delvos U, Meusel P, Preissner KT, Muller BerghausG. Formation of activated protein C and inactivation of cell-bound thrombin by antithrombin III at the surface of cultured vascular endothelial cells—a comparative study of two anticoagulant mechanisms. Thromb Haemost 1987; 57: 87-91
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Bird AP. CpG-rich islands and the function of DNA methyla- tion. Nature 1986; 321: 209-213
    CrossrefPubMedGoogle Scholar
  • 51 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
    CrossrefPubMedGoogle Scholar
  • 52 Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 19 (02) 1165-1168
    PubMedGoogle Scholar
  • 53 Estelles A, Garcia PlazaI, Dasi A, Aznar J, Duart M, Sanz G, Perez RequejoJL, Espana F, Jimenez C, Abeledo G. Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984; 52: 53-56
    PubMedGoogle Scholar
  • 54 Seligsohn U, Berger A, Abend M, Rubin L, Attias D, Zivelin A, Rapaport SI. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559-562
    CrossrefPubMedGoogle Scholar
  • 55 Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood 1985; 65: 15-20
    PubMedGoogle Scholar
  • 56 Miletich J, Sherman L, Broze Jr. G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996
    CrossrefPubMedGoogle Scholar
  • 57 Hallam PJ, Millar DS, Krawczak M, Kakkar VV, Cooper DN. Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency. J Med Genet 1995; 32: 543-545
    CrossrefPubMedGoogle Scholar
  • 58 Koster T, Rosendaal FR, Briët E, Van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: An infrequent but clear risk factor for venous thrombosis (Leiden thrombophilia study). Blood 1995; 85: 2756-2761
    CrossrefPubMedGoogle Scholar
  • 59 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-1035
    PubMedGoogle Scholar
  • 60 Conard J, Horellou MH, Van DredenP, Samama M, Reitsma PH, Poort SR, Bertina RM. Homozygous protein C deficiency with late onset and recurrent coumarin-induced skin lesions. Lancet 1992; 339: 743-744
    CrossrefPubMedGoogle Scholar
  • 61 Grundy CB, Melissari E, Lindo V, Scully MF, Kakkar VV, Cooper DN. Late-onset homozygous protein C deficiency. Lancet 1991; 338: 575-576
    PubMedGoogle Scholar
  • 62 Long GL, Tomczak JA, Rainville IR, Dreyfus M, Schramm W, Schwarz HP. Homozygous type 1 protein C deficiency in two unrelated families exhibiting thrombophilia related to Alai 36→Pro or Arg286→His mutations. Thromb Haemost 1994; 72: 526-533
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Soria JM, Brito D, Barcelo J, Fontcuberta J, Botero L, Maldonado J, Estivill X, Sala N. Severe homozygous protein C deficiency: identification of a splice site missense mutation (184, Q→H) in exon 7 of the protein C gene. Thromb Haemost 1994; 72: 65-69
    PubMedGoogle Scholar
  • 64 Witt I, Beck S, Seydewitz HH, Tasangil C, Schenck W. A novel homozygous missense mutation (Val 325→Ala) in the protein C gene causing neonatal purpura fulminans. Blood Coagul Fibrinolysis 1994; 05: 651-653
    PubMedGoogle Scholar
  • 65 Millar DS, Allgrove J, Rodeck C, Kakkar VV, Cooper DN. A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy. Blood Coagul Fibrinolysis 1994; 05: 647-649
    PubMedGoogle Scholar
  • 66 Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planché C, Dehan M, Tchernia G. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325: 1565-1568
    CrossrefPubMedGoogle Scholar
  • 67 Gandrille S, Jude B, Alhenc-Gelas M, Millaire A, Aiach M. Compound heterozygosity in a family with protein C deficiency illustrating the complexity of the underlying molecular mechanism. Thromb Haemost 1993; 70: 747-752
    Article in Thieme ConnectPubMedGoogle Scholar
  • 68 Sugahara Y, Miura O, Hirosawa S, Aoki N. Compound heterozygous protein C deficiency caused by two mutations Arg-178 to Gin and Cys-331 to Argleading to impaired secretion of mutant protein C. Thromb Haemost 1994; 72: 814-818
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb 1995; 15: 214-218
    CrossrefPubMedGoogle Scholar