Protein C Deficiency: A Database of Mutations, 1995 Update

P H Reitsma; F Bernardi; R G Doig; S Gandrille; J S Greengard; H Ireland; M Krawczak; B Lind; G L Long; S R Poort; H Saito; N Sala; I Witt; D N Cooper

doi:10.1055/s-0038-1653885

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 73(05): 876-889
DOI: 10.1055/s-0038-1653885

Scientific and Standardization Committee Communications

Schattauer GmbH Stuttgart

Protein C Deficiency: A Database of Mutations, 1995 Update

On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH

P H Reitsma

¹the hemostasis and Thrombosis Research Center, University Hospital, Leiden, The Netherlands

,

F Bernardi

²Dipartimento Biochimica e Biologia Moleculare, Università degli studi di Ferrara, Ferrara, Italy

,

R G Doig

³Diagnostic Haematology, The Royal Melbourne Hospital, Victoria, Australia

,

S Gandrille

⁴INSERM CJF 91-01, UFR des Sciences Pharma- ceutiques et Biologiques, Paris, France

,

J S Greengard

⁵Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA

,

H Ireland

⁶Department of Haematology, Charing Cross & Westminster Medical School, London, UK

,

M Krawczak

⁷Abteilung Humangenetik, Medizinische Hochschule, Hannover, Germany

,

B Lind

⁸Section for Hemostasis and Thrombosis, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark

,

G L Long

⁹Department of Biochemistry, School of Medicine, University of Vermont, Burlington, VT, USA

,

S R Poort

¹the hemostasis and Thrombosis Research Center, University Hospital, Leiden, The Netherlands

,

H Saito

¹⁰First Department of Internal Medicine, Nagoya University School of Medicine, Tsurumai-cho, Nagoya, Japan

,

N Sala

¹¹Cancer Research Institute, Hospital Duran I Reynals, Barcelona, Spain

,

I Witt

¹²Biochemisches Labor, Universitäts-Kinderklinik Freiburg, Freiburg, Germany

,

D N Cooper

¹³Charter Molecular Genetics Laboratory, Thrombosis Research Institute, London, UK

› Author Affiliations

Abstract

PDF Download

PDF (1490 kb)

References

References
1 Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost 1994; 70: 29-35
2 Dahlbäck B, Stenflo J. A natural anticoagulant pathway: proteins C, S, C4b-binding protein and thrombomodulin. In: Haemostasis and Thrombosis. Bloom AL, Forbes CD, Thomas DP, Tuddenham EG D. eds Edinburgh: Churchill Livingstone; 1994. pp 671-698
3 Tuddenham EG D, Cooper DN. The molecular genetics of haemostasis and its inherited disorders. Oxford: Oxford University Press; 1994
4 Foster D, Davie EW. Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci USA 1984; 81: 4766-4770
5 Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL. The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs. Nucleic Acids Res 1985; 13: 5233-5247
6 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
7 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
8 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
9 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
10 Spek CA, Poort SR, Bertina RM, Reitsma PH. Determination of the allelic and haplotype frequences of three polymorphisms in the promoter region of the human protein C gene. Blood Coagul Fibrinolysis 1994; 5: 309-311
11 Tsay W, Greengard JS, Griffin JH. Exonic polymorphisms in the protein C gene: interethnic comparison between Caucasians and Asians. Hum Genet 1994; 94: 177-178
12 Long GL, Belagaje RM, MacGillivray RT. Cloning and sequencing of liver cDNA coding for bovine protein C. Proc Natl Acad Sci US A 1984; 81: 5653-5656
13 Okafuji T, Maekawa K, Nawa K, Marumoto Y. The cDNA cloning and mRNA expression of rat protein C. Biochim Biophys Acta 1992; 1131: 329-332
14 Tada N, Sato M, Tsujimura A, Iwase R, Hashimoto-Gotoh T. Isolation and characterization of a mouse protein C cDNA. J Biochem (Tokyo) 1992; 111: 491-495
15 Murakawa M, Okamura T, Kamura T, Kuroiwa M, Harada M. A comparative study of partial primary structures of the catalytic region of mammalian protein C. Br J Haematol 1994; 86: 590-600
16 Broekmans AW, Conard J. Hereditary protein C deficiency. In: Protein C and related proteins. Bertina RM. ed Edinburgh: Churchill Livingstone; 1988. pp 160-181
17 Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988; 59: 18-22
18 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
19 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-717
20 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-138
21 Henkens CM A, Van derMeer, Hillege JL, Van derSchaaf, Bom VJ, Halie MR. The clinical expression of hereditary protein C and protein S deficiency: a relation to clinical thrombotic risk factors and to levels of protein C and protein S. Blood Coagul Fibrinolysis 1993; 4: 555-562
22 Mannucci PM, Vigano S, Bottasso B, Candotti G, Bozzetti P, Rossi E, Pardi G. Protein C antigen during pregnancy, delivery and puerperium. Thromb Haemost 1984; 52: 217
23 Meade TW, Stirling Y, Wilkes H, Mannucci PM. Effects of oral contraceptives and obesity on protein C antigen. Thromb Haemost 1985; 53: 198-199
24 Bertina RM, Koeleman BP C, Koster T, Rosendaal FR, Dirven RJ, De RondeH, Van derVelden, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 364-7
25 Koeleman BP C, Reitsma PH, Allaart CF, Bertina RM. APC-resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-1035
26 Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiencyReport of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989; 114: 528-534
27 Tuddenham EG, Takase T, Thomas AE, Awidi AS, Madanat FF, Abu HajirM, Kernoff PB, Hoffbrand AV. Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 1989; 53: 475-484
28 Wacey AI, Pemberton S, Cooper DN, Kakkar VV, Tuddenham EG D. 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
29 Greengard JS, Fisher CL, Villoutreix B, Griffin JH. Structural basis for type I and type II déficiences of antithrombotic plasma protein C: patterns revealed by three-dimensional molecular modeling of mutations of the protease domain. Proteins: Struct Func Genet 1994; 18: 367-380
30 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 (GlyySer) in the substrate-binding pocket of serine proteases. Br J Haematol 1993; 84: 285-289
31 Cooper DN, Krawczak M. Human gene mutation. Oxford: Bios Scientific; 1994
32 Lind B, Van SolingeW, Schwartz M, Thorsen S. Splice site mutation in the human protein C gene associated with venous thrombosis: Demonstration of exon skipping by ectopic transcript analysis. Blood 1993; 82: 2423-2432
33 Berg L-P, 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; 3: 2147-2152
34 Matsuda M, Sugo T, Sakata Y, Murayama H, Mimuro J, Tanabe S, Yoshi-take S. A thrombotic state due to an abnormal protein C. N Engl J Med 1988; 319: 1265-1268
35 Krawczak M, Reitsma PH, Cooper DN. The mutational demography of protein C deficiency. Hum Genet. 1995 (in press)
36 Greengard JS, Tsay W, Montgomery R, Heeb MJ, Griffin JH. 1994 Personal communication.
37 Poort SR, Pabinger-Fasching I, Mannhalter C, Reitsma PH, Bertina RM. Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency. Blood Coagul Fibrinolysis 1993; 4: 273-280
38 Millar DS, Grundy CB, Bignell P, Mitchell DC, Corden D, Woods P, Kakkar VV, Cooper DN. A novel nonsense mutation in the protein C gene (Trp-29-Term) causing recurrent venous thrombosis. Hum Genet 1993; 91: 196
39 Soria JM, Sala N. 1994 Personal communication.
40 Tomczak JA, Broxson EH, Marlar RA, Long GL. Association of two novel intron mutations with familial type one protein C deficiency. Thromb Haemost 1993; 69: 721 (Abstract)
41 Tait RC, Walker ID, Reitsma PH, Islam SI A M, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93
42 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 modeling. Blood Coagul Fibrinolysis 1994; 5: 687-696
43 Gandrille S, Aiach M. and the French INSERM Network on “the Molecular Basis of Protein C and Protein S hereditary deficiencies”. 1994 Personal communication
44 Millar DS, Cooper DN. 1994 Personal communication.
45 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
46 Long GL. 1994 Personal communication.
47 Ireland H, Thompson E, Taylor J, Boisclair MD, Lane DA, Girolami A, De-Caterina M, DeStefano V, Leone G, Finazzi G, Cohen H. Molecular basis of protein C deficiency in five families with thrombophilia. Blood Coagul Fibrinolysis 1993; 4: 351 (Abstract)
48 Ireland H, Lane DA. 1994 Personal communication.
49 Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Heilmann M, Toulon P, Fiessinger JN, Goossens M. Two novel mutations responsible for type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. Hum Mut 1993; 1: 491-500
50 Sala N, Poort SR, Bertina RM, Soria JM, Fontcuberta J, Reitsma PH. Identification of two deletions and four point mutations in the protein C gene of 6 unrelated Spanish patients with hereditary protein C deficiency. Thromb Haemost 1991; 65: 1197 (Abstract)
51 Gandrille S, Alhenc-Gelas M, Aillaud MF, Dupuy E, Aiach M. Protein C hereditary qualitative deficiency due to an arginine -1 to cysteine mutation in propeptide. Circulation 1992; 86: 2934 (Abstract)
52 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
53 Gandrille S, Alhenc-Gelas M, Goossens M, Aiach M, Malakoff PC. An abnormal protein C due to mutation at the cleavage site of the propeptide. Thromb Haemost 1991; 65: 1196 (Abstract)
54 Lind B, Schwartz M, Thorsen S. Six different missense mutations in seven Danish families with symptomatic protein C deficiency. Thromb Haemost 1993; 69: 2540 (Abstract)
55 Poort SR, Bertina RM, Reitsma PH. 1994 Personal communication.
56 Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Hellman M, Toulon P, Goossens M. Six previously undescribed mutations in 9 families with protein C quantitative deficiency. Thromb Haemost 1991; 65: 646 (Abstract)
57 Mimuro J, Matsumura S, Kaneko M, Yoshitake S, Iijima K, Nakamura K, Sakata Y, Matsuda M. An abnormal protein C (protein C Yonago) with an amino acid substitution of Gly for Arg-15 caused by a single base mutation of C to G in codon 57 (CGG-→GGG): detoriated calcium-dependent conformation of the Γ-carboxy-glutamic acid domain relative to thrombotic tendency. Int J Haematol 1993; 57: 9-14
58 Bovill EG, Tomczak JA, Grant B, Bhushan F, Pillemer E, Rainville IR, Long GL. Protein C_Vermont: Symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood 1992; 79: 1456-1465
59 Greengard JS, Tsay W, Vicente V, Griffin JH. 1994 Pers.comm.
60 Ido M, Ohiwa M, Hayashi T, Nishioka J, Hatada T, Watanabe Y, Wada H, Shirakawa S, Suzuki K. A compound heterozygous protein C deficiency with a single nucleotide G deletion encoding Gly-381 and an amino acid substitution of Lys for Gla-26. Thromb Haemost 1993; 70: 636-641
61 Koster T, Rosendaal FR, Van der Meer FJ M, Colly LP, Trienekens PH, Poort SR, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis. Leiden Thrombophilia Study (LETS). Blood 1995 (in press)
62 Soria JM, Fontcuberta J, Borrell M, Estivill X, Sala N. Two novel mutations in exon 5 of the protein C gene in two Spanish families with thrombophilia due to protein C deficiency. Hum Mol Genet 1994; 3: 1205-1206
63 Tsay W, Greengard JS, Montgomery R, Griffin JH. Five previously undescribed mutations in protein C (PC) that identify elements critical for gene and protein activity. Blood 1991; 78: 184a (Abstract)
64 Poort SR, Reitsma PH. 1994 Personal communication.
65 Witt I. 1994 Personal communication.
66 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
67 Tsuda S, Reitsma PH, Miletich J. Molecular defects causing heterozygous protein C deficiency in three asymptomatic kindreds. Thromb Haemost 1991; 65: 647 (Abstract)
68 Sala N, Soria JM, Borrell M, Navarro G, Fontcuberta J, Estivill X. Estudio de la mutacion causante del deficit cualitativo de PC en tres familias. Sangre 1993; 38: 20 (Abstract)
69 Doig RG. 1994 Personal communication.
70 Soria JM, Fontcuberta J, Chillón M, Borrell M, Estivill X, Sala N. Acceptor splice site mutation in the invariant AG of intron 5 of the protein C gene, causing type I protein C deficiency. Hum Genet 1993; 92: 506-508
71 Tomczak JA, Ando RA, Sobel HG, Bovill EG, Long GL. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res 1994; 74: 243-54
72 Estelles A, Garcia PlazaI, Dasi A, Aznar J, Duart M, Sanz G, Perez RequejoJ, Espana F, Jimenez C, Abeledo G. Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984; 52: 53-56
73 Sugahara Y, Miura O, Yuen P, Aoki N. Protein C deficiency Hong Kong 1 and 2: Hereditary protein C deficiency caused by two mutant alleles, a 5-nucleotide deletion and a missense mutation. Blood 1992; 80: 126-133
74 Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planch C, Dehan M, Tchemia 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
75 Long GL, Tomczak JA, Rainville IR, Dreyfus M, Schramm W, Schwarz HP. Homozygous protein C deficiency in two unrelated families exhibiting thrombophilia related to Alal366Pro or Arg2868His mutations. Thromb Haemost 1994; 72: 526-533
76 Witt I, Seydewitz HH, Asbeck D, Beck S, Nabel C. Protein C gene mutations in ten unrelated families with symptomatic protein C deficiency. Ann Hematol 1994; 68: 58 (Abstract)
77 Soria JM, Fontcuberta J, Borrell M, Estivill X, Sala N. Protein C deficiency: identification of a novel two-base pair insertion and two point mutations in exon 7 of the protein C gene in Spanish families. Hum Mut 1992; 1: 428-431
78 Grundy C, Plendl H, Grote W, Zoll B, Kakkar VV, Cooper DN. A single base-pair deletion in the protein C gene causing recurrent thromboembolism. Thromb Res 1991; 61: 335-340
79 Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Hellman M, Toulon P, Goossens M. Quantitative hereditary protein C deficiency: identification of two novel mutations at CpG sites in exon VI of the protein C gene. Blood 1990; 76: 2018 (Abstract)
80 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
81 Nesbitt IM, Winship PR, Preston FE, Peake IR. Mutation at the thrombin activation site of protein C in a protein C deficient family. Proc 24th Int Soc Haematol; London: 1992: 40 (Abstract)
82 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; 17: 10513
83 Grundy CB, Schulman S, Tengbom 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; 89: 685-686
84 Hertfelder H-J, Poort SR, Reitsma PH. 1994 Personal communication.
85 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, QQH) in exon 7 of the protein C gene. Thromb Haemost 1994; 72: 65-69
86 Sala N, Borrell M, Bauer KA, Vigano S, Fontcuberta J, Felez J, Rutilant ML. Dysfunctional activated protein C (PC Cadiz) in a patient with thrombotic disease. Thromb Haemost 1987; 57: 183-186
87 Soria JM, Fontcuberta J, Brito D, Estivill X, Sala N. The use of SSCP’s in the analysis of the protein C gene: identification of six different mutations in protein C deficient Spanish families. Thromb Haemost 1993; 69: 720 (Abstract)
88 Gandrille S, Jude B, Alhenc-Gelas M, Milaire A, Aiach M. Compound heterozygosity in a family with quantitative protein C deficiency due to the association of Leu 223 to Phe and lie 403 to Met mutations. Thromb Haemost 1993; 69: 1281 (Abstract)
89 Gandrille S, Alhenc-Gelas M, Juhan-Vague I, Fiessinger JN, Goossens M, Aiach M. Two qualitative protein C (PC) deficiencies due to Arg29→Gln (PC Marseille) and Ser252-→Asn (PC Paris) mutations. Thromb Haemost 1991; 65: 1196 (Abstract)
90 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolismA study of three Dutch families. N Engl J Med 1983; 309: 340-344
91 Bertina RM, Broekmans AW, van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost 1982; 48: 1-5
92 Grundy CB, Melissari E, Lindo V, Scully MF, Kakkar VV, Cooper DN. Late-onset homozygous protein C deficiency. Lancet 1991; 338: 575-576
93 Gandrille S, Alhenc-Gelas M, Emmerich J, Fiessinger JN, Aiach M. A de novo mutation responsible for type I protein C deficiency. Thromb Haemost 1993; 69: 1282 (Abstract)
94 Yamamoto K, Matsushita T, Sugiura I, Takamatsu J, Iwasaki E, Wada H, Deguchi K, Shirakawa S, Saito H. Homozygous protein C deficiency: Identification of a novel missense mutation that causes impaired secretion of the mutant protein C. J Lab Clin Med 1992; 119: 682-689
95 Millar DS, Wacey AI, Voke J, Kakkar VV, Cooper DN. A novel point mutation (Val 2977Met) 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
96 Bemardi F, Patracchini P, Gemmati D, Boninsegna S, Guerra S, Legnani C, Ballerini G, Marchetti G. Rapid detection of a protein C mutation present in the asymptomatic and not in the thrombosis-prone lineage. BrJ Haematol 1992; 81: 277-282
97 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 USA 1987; 84: 2829-2832
98 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
99 Gandrille S, Alhenc-Gelas M, Gaussem P, Aillaud M-F, Dupuy E, Juhan-Vague I, Aiach M. Five novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity. Blood 1993; 82: 159-168
100 Witt I, Seydewitz HH, Tasangil C, Schenk W. A novel homozygous missense mutation (Val3255Ala) in the protein C gene causing neonatal purpura fulminans. Blood Coagul Fibrinolysis 1994; 5: 651-653
101 Yamamoto K, Tanimoto M, Emi N, Matsushita T, Takamatsu J, Saito H. Impaired secretion of the elongated mutant of protein C (protein C-Nagoya); molecular and cellular basis for hereditary protein C deficiency. J Clin Invest 1992; 90: 2439-2446
102 Tokunaga F, Wakabayashi S, Sato H, Arakawa M, Tawaraya H, Koide T. Identification of one base deletion in exon IX of the protein C gene that causes a type I deficiency. Thromb Res 1992; 68: 417-423
103 Miyata T, Zheng YZ, Sakata T, Tsushima N, Kato H. Three missense mutations in the protein C heavy chain causing type I and type II protein C deficiency. Thromb Haemost 1994; 71: 32-37
104 Gonzalez R, Alberca I, Sala N, Vicente V. Protein C deficiency -response to danazol and DDAVP. Thromb Haemost 1985; 53: 320-322
105 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
106 Bertina RM, Broekmans AW, Krommenhoek van Es C, van Wijngaarden A. The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemost 1984; 51: 1-5
107 Sala N, Owen WG, Collen D. A functional assay of protein C in human plasma. Blood 1984; 63: 671-675
108 Gaussem P, Gandrille S, Duchemin J, Alhenc-Gelas M, Aillaud MF, Aiach M. Influence of six mutations of the protein C gene on the GLA domain conformation and calcium affinity. Thromb Haemost 1994; 71: 748-754
109 Gandrille S, Goossens M, Aiach M. A scanning method to establish the molecular basis of protein C deficiencies. Human Mutation 1994; 4: 20-30
110 Gandrille S, Jude B, Alhenc-Gelas M, Emmerich J, Aiach M. First de novo mutations in two patients with type I deficiency: a missense mutation and a splice site deletion. Blood 1994; 84: 2566-2570
111 Millar DS, Grundy CB, Bignell P, Moffat EH, Martin R, Kakkar VV, Cooper DN. A Gla domain mutation (Argl5_Trp) in the protein C gene causing type 2 protein C deficiency and recurrent venous thrombosis. Blood Coagul Fibrinolysis 1993; 4: 345-347
112 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 in an at-risk pregnancy. Blood Coagul Fibrinolysis 1994; 5: 647-679