Three Missense Mutations in the Protein C Heavy Chain Causing Type I and Type II Protein C Deficiency

Toshiyuki Miyata; Yan-Zhen Zheng; Toshiyuki Sakata; Nobuko Tsushima; Hisao Kato

doi:10.1055/s-0038-1642381

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1994; 71(01): 032-037
DOI: 10.1055/s-0038-1642381

Review Article

Schattauer GmbH Stuttgart

Three Missense Mutations in the Protein C Heavy Chain Causing Type I and Type II Protein C Deficiency

Authors

Toshiyuki Miyata

¹The Laboratory of Thrombosis Research and Division of Etiology and Pathogenesis, National Cardiovascular Center Research Institute, Fujishirodai 5, Suita 565, Japan
Yan-Zhen Zheng

¹The Laboratory of Thrombosis Research and Division of Etiology and Pathogenesis, National Cardiovascular Center Research Institute, Fujishirodai 5, Suita 565, Japan
Toshiyuki Sakata

²Department of Clinical Laboratory, National Cardiovascular Center, Fujishirodai 5, Suita 565, Japan
Nobuko Tsushima

³Department of Medicine, National Cardiovascular Center, Fujishirodai 5, Suita 565, Japan
Hisao Kato

¹The Laboratory of Thrombosis Research and Division of Etiology and Pathogenesis, National Cardiovascular Center Research Institute, Fujishirodai 5, Suita 565, Japan

Abstract

PDF Download

Summary

We have studied the molecular basis of protein C deficiency in three families with a history of thromboembolic disease. An approximately 50% reduction in both functional and immunologic levels of protein C was detected in the plasma from two unrelated patients, designated protein C Osaka 1 and protein C Osaka 2. An approximately 50% reduction in functional level but normal immunologic level of protein C was detected in plasma from a third patient, designated protein C Osaka 3. DNA sequencing of the amplified DNA revealed one missense mutation in each case. Additional mutations in the coding sequence were excluded by DNA sequencing of all protein C exons. We identified a C-to-T change at nucleotide number 6,218 of the protein C gene in protein C Osaka 1. This results in the amino acid substitution of Arg-169 by Trp at the a-thrombin cleavage site. In protein C Osaka 2, a G-to-A change at nucleotide number 8,807 was identified leading to the amino acid substitution of Met-364 by lie in the protease domain. This substitution may impair the synthesis or stability of protein C Osaka 2. In protein C Osaka 3, a G-to-C change at nucleotide number 8,868 was identified. This results in substitution of Gly-385 by Arg in the protease domain. Based on these, it was concluded that Arg-169-to-Trp mutation and Met-364-to-Ile mutation cause type I protein C deficiency and Gly-385-to-Arg mutation causes type II deficiency.

PDF (271 kb)

References

References
1 Stenflo J. A new vitamin K-dependent protein: Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251: 355-63
2 Kisiel W, Ericsson LH, Davie EW. Proteolytic activation of protein C from bovine plasma. Biochemistry 1976; 15: 4893-900
3 Esmon CT. Protein-C: Biochemistry, physiology, and clinical implications. Blood 1983; 62: 1155-8
4 Foster D, Davie EW. Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci USA 1984; 81: 4766-70
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. Nucl Acid Res 1985; 13: 5233-47
6 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985; 82: 4673-7
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: 546-50
8 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-31
9 Vehar GA, Davie EW. Preparation and properties of bovine factor VIII (antihemophilic factor). Biochemistry 1980; 19: 401-10
10 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-72
11 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3
12 Pabinger-Fasching I, Bertina RM, Lechner K, Niessner H, Korninger Ch. Protein C deficiency in two Austrian families. Thromb Haemostas 1983; 50: 810-3
13 Brockmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: A study of three Dutch families. N Engl J Med 1983; 309: 340-4
14 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: 712-7
15 Horellou MH, Conard J, Bertina RM, Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J 1984; 289: 1285-7
16 Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C, Cortese R. Hereditary thrombophilia: Identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci USA 1987; 84: 2829-32
17 Matsuda M, Sugo T, Sakata Y, Murayama H, Mimuro J, Tanebe S, Yoshitake S. A thrombotic state due to an abnormal protein C. N Engl J Med 1988; 319: 1265-8
18 Reitsma PH, Poort SR, Allaart CF, Briet AE, 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: 890-4
19 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. Nucl Acid Res 1989; 17: 105-13
20 Bovill EG, Tomczak JA, Grant BN, 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: 1456-65
21 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: 126-33
22 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: 2439-46
23 Bernardi F, Patracchini P, Gemmati D, Boninsegna S, Guerra S, Legnani C, Ballerini G, Marchetti G. Rapid detection of a protein C gene mutation present in the asymptomatic and not in the thrombosisprone lineage. Br J Haematol 1992; 81: 277-82
24 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: 417-23
25 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
26 Sakata T, Tsushima N, Hatanaka K, Morishita T, Hatsuyama H, Uchida K, Katayama Y, Matsuyama T. Probable dysfunctional protein S in a patient with congenital heterozygous protein C deficiency: A family study. Jpn J Thromb Hemostas 1991; 2: 518-23
27 Bell GI, Karam JH, Rutter WJ. Polymorphic DNA region adjacent to the 5’ end of the human insulin gene. Proc Natl Acad Sci USA 1981; 78: 5759-63
28 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-91
29 Orita M, Suzuki Y, Sekiya X, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 1989; 5: 874-9
30 Yamamoto K, Tanimoto M, Matsushita T, Kagami K, Sugiura I, Hamaguchi M, Takamatsu J, Saito H. Genotype establishments for protein C deficiency by use of a DNA polymorphism in the gene. Blood 1991; 77: 2633-6
31 Barker D, Schafer M, White R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 1984; 36: 131-8
32 Cooper DN, Youssoufian H. The CpG dinucleotide and human disease. Hum Genet 1988; 78: 151-5
33 Long GL, Belagaje RM, MacGillivray RT A. Cloning and sequencing of liver cDNA coding for bovine protein C. Proc Natl Acad Sci USA 1984; 81: 5653-6
34 Tada N, Sato M, Tsujimura A, Iwase R, Hashimoto-Gotoh T. Isolation and characterization of a mouse protein C cDNA. J Biochem 1992; 111: 491-5
35 Okafuji T, Maekawa K, Nawa K, Marumoto Y. The cDNA cloning and mRNA expression of rat protein C. Biochim Biophys Acta 1992; 1131: 329-32
36 Giannelli F, Green PM, High KA, Sommer S, Lillicrap DP, Ludwig M, Olek K, Reitsma PH, Goossens M, Yoshioka A, Brownlee GG. Haemophilia B: database of point mutations and short additions and deletions – third edition, 1992. Nucl Acid Res 1992; 20: 2027-63
37 Degen SJ F, MacGillivray RT A, Davie EW. Characterization of the complementary deoxyribonucleic acid and gene coding for human prothrombin. Biochemistry 1983; 22: 2087-97
38 Leytus SP, Foster DC, Kurachi K, Davie EW. Gene for human factor X: A blood coagulation factor whose gene organization is essentially identical with that of factor IX and protein C. Biochemistry 1986; 25: 5098-102
39 Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985; 24: 3736-50
40 Hagen FS, Gray CL, O’Hara P, Grant FJ, Saari GC, Woodbury RG, Hart CE, Insley M, Kisiel W, Kurachi K, Davie EW. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci USA 1986; 83: 2412-6
41 Walsh KA. Trypsinogens and trypsins of various species. Methods Enzymol. Perlmann GE, Lorand L. (eds) Academic Press; New York: 1970. (; 19). 41-63
42 Wilcox PE. Chymotrypsinogens – chymotrypsin. Methods Enzymol. Perlmann GE, Lorand L. (eds) Academic Press; New York: 1970. (; 19). 64-108
43 Sugimoto M, Miyata T, Kawabata S, Yoshioka A, Fukui H, Takahashi H, Iwanaga S. Blood clotting factor IX Niigata: Substitution of alanine-390 by valine in the catalytic domain. J Biochem 1988; 104: 878-80
44 Spitzer SG, Pendurthi UR, Kasper CK, Bajaj SP. Molecular defect in factor IX _{Bm Lake Elsinore}. Substitution of Ala³⁹⁰ by Val in the catalytic domain. J Biol Chem 1988; 263: 10545-8
45 Tarnower A, Gribble TJ, Smith KJ. Molecular basis of hemophilia B in New Mexico, U.S. A. Thromb Haemost 1991; 65: 967