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DOI: 10.1055/s-0037-1613167
A Single Thymine Nucleotide Deletion Responsible for Congenital Deficiency of Plasmin Inhibitor
Publikationsverlauf
Received
20. Dezember 2001
Accepted after resubmission
18. April 2002
Publikationsdatum:
09. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200201/lookinside/thumbnails/10-1055-s-0037-1613167-1.jpg)
Summary
Plasma plasmin inhibitor (PI) is a physiological inhibitor of plasminmediated fibrinolysis and constitutes a hemostatic component in blood plasma; hence its deficiency results in a severe hemorrhagic diathesis. We have carried out molecular analysis of American family members with congenital PI deficiency, and detected a single thymine deletion at nucleotide position 332 in exon 5. The deletion was found in both alleles of the homozygotes and in one allele of the heterozygotes, and the patterns of restriction fragment length polymorphism created by the mutation in the family members were compatible with their phenotypes. The deletion caused a frameshift leading to an alteration and shortening of the deduced amino acid sequence. The amino acid sequence consists of the first 83 amino acids of the N-terminal sequence of the normal PI and additional new amino acids, resulting in a mutant composed of 94 amino acids in contrast to 464 amino acids of the normal PI. In transient expression analysis, the mutant PI whose molecular size was compatible with the predicted amino acid sequence was detected in the lysates of the cells transfected with the mutated PI expression vector. The mutant PI was retained and underwent progressive degradation within the cells, and was minimally excreted into the media. These data indicate that this mutation is the cause of PI deficiency in this pedigree.
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References
- 1 Blombäck M, Abildgaard U, van den Besselaar AM, Clementson KJ, Dahlbäck B, Exner T, Francis CW, Gaffney P, Gralnick H, Hoyer LW. et al. Nomenclature of quantities and units in thrombosis and haemostasis (recommendation 1993). A Collaborative project of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH/SSC) and the Commission/Committee on Quantities and Units (in Clinical Chemistry) of the International Union of Pure and Applied Chemistry-International Federation of Clinical Chemistry (IUPAC-IFCC/CQU(CC)). Thromb Haemost 1994; 71: 375-94.
- 2 Moroi M, Aoki N. Isolation and characterization of α2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activatorinduced clot lysis. J Biol Chem 1976; 251: 5956-65.
- 3 Wiman B, Collen D. Purification and characterization of human antiplasmin, the fast-acting plasmin inhibitor in plasma. Eur J Biochem 1977; 78: 19-26.
- 4 Bangert K, Johnsen AH, Christensen U, Thorsen S. Different N-terminal forms of α2-plasmin inhibitor in human plasma. Biochem J 1993; 291: 623-5.
- 5 Koyama T, Koike Y, Toyota S, Miyagi F, Suzuki N, Aoki N. Different NH2-terminal form with 12 additional residues of α2-plasmin inhibitor from human plasma and culture media of Hep G2 cells. Biochem Biophys Res Commun 1994; 200: 417-22.
- 6 Hirosawa S, Nakamura Y, Miura O, Sumi Y, Aoki N. Organization of the human α2-plasmin inhibitor gene. Proc Natl Acad Sci USA 1988; 85: 6836-40.
- 7 Kato A, Hirosawa S, Toyota S, Nakamura Y, Nishi H, Kimura A, Sasazuki T, Aoki N. Localization of the human α2-plasmin inhibitor gene (PLI) to 17p13. Cytogenet Cell Genet 1993; 62: 190-1.
- 8 Welch SK, Francke U. Assignment of the human α2-plasmin inhibitor gene (PLI) to chromosome 17, region pter-p12, by PCR analysis of somatic cell hybrids. Genomics 1992; 13: 213-4.
- 9 Aoki N, Moroi M, Matsuda M, Tachiya K. The behavior of α2-plasmin inhibitor in fibrinolytic states. J Clin Invest 1977; 60: 361-9.
- 10 Aoki N, Moroi M, Tachiya K. Effects of α2-plasmin inhibitor on fibrin clot lysis. Its comparison with α2-macroglobulin. Thromb Haemost 1978; 39: 22-31.
- 11 Clemmensen I, Thorsen S, Mullertz S, Petersen LC. Properties of three different molecular forms of the α2-plasmin inhibitor. Eur J Biochem 1981; 120: 105-12.
- 12 Aoki N, Sakata Y, Ichinose A. Fibrin-associated plasminogen activation in α2-plasmin inhibitor deficiency. Blood 1983; 62: 1118-22.
- 13 Sakata Y, Aoki N. Cross-linking of cx2-plasmin inhibitor to fibrin by fibrin-stabilizing factor. J Clin Invest 1980; 65: 290-7.
- 14 Tamaki T, Aoki N. Cross-linking of α2-plasmin inhibitor to fibrin catalyzed by activated fibrin-stabilizing factor. J Biol Chem 1982; 257: 14767-72.
- 15 Kimura S, Aoki N. Cross-linking site in fibrinogen for α2-plasmin inhibitor. J Biol Chem 1986; 261: 15591-5.
- 16 Sakata Y, Aoki N. Significance of cross-linking of α2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69: 536-42.
- 17 Jansen JW, Haverkate F, Koopman J, Nieuwenhuis HK, Kluft C, Boschman TA. Influence of factor XIIIa activity on human whole blood clot lysis in vitro. Thromb Haemost 1987; 57: 171-5.
- 18 Reed 3rd GL, Matsueda GR, Haber E. Inhibition of clot-bound α2-antiplasmin enhances in vivo thrombolysis. Circulation 1990; 82: 164-8.
- 19 Aoki N, Sakata Y, Matsuda M, Tateno K. Fibrinolytic states in a patient with congenital deficiency of α2-plasmin inhibitor. Blood 1980; 55: 483-8.
- 20 Aoki N. Genetic abnormalities of the fibrinolytic system. Semin Thromb Hemostas 1984; 10: 42-50.
- 21 Saito H. α2-plasmin inhibitor and its deficiency states. J Lab Clin Med 1988; 112: 671-8.
- 22 Favier R, Aoki N, de Moerloose P. Congenital α2-plasmin inhibitor deficiencies: a review. Br J Haematol 2001; 114: 4-10.
- 23 Miura O, Hirosawa S, Kato A, Aoki N. Molecular basis for congenital deficiency of α2-plasmin inhibitor. A frameshift mutation leading to elongation of the deduced amino acid sequence. J Clin Invest 1989; 83: 1598-604.
- 24 Miura O, Sugahara Y, Aoki N. Hereditary α2-plasmin inhibitor deficiency caused by a transport-deficient mutation (α2-PI-Okinawa). Deletion of Glu137 by a trinucleotide deletion blocks intracellular transport. J Biol Chem 1989; 264: 18213-9.
- 25 Miura O, Aoki N. Impaired secretion of mutant α2-plasmin inhibitor (α2PINara) from COS-7 and HepG2 cells: molecular and cellular basis for hereditary deficiency of α2-plasmin inhibitor. Blood 1990; 75: 1092-6.
- 26 Lind B, Thorsen S. A novel missense mutation in the human plasmin inhibitor (α2-antiplasmin) gene associated with a bleeding tendency. Br J Haematol 1999; 107: 317-22.
- 27 Yoshinaga H, Hirosawa S, Chung DH, Miyasaka N, Aoki N, Favier R. A novel point mutation of the splicing donor site in the intron 2 of the plasmin inhibitor gene. Thromb Haemost 2000; 84: 307-11.
- 28 Holmes WE, Lijnen HR, Nelles L, Kluft C, Nieuwenhuis HK, Rijken DC, Collen D. α2-antiplasmin Enschede: alanine insertion and abolition of plasmin inhibitory activity. Science 1987; 238: 209-11.
- 29 Miles LA, Plow EF, Donnelly KJ, Hougie C, Griffin JH. A bleeding disorder due to deficiency of α2-antiplasmin. Blood 1982; 59: 1246-51.
- 30 Mimuro J, Koike Y, Sumi Y, Aoki N. Monoclonal antibodies to discrete regions in α2-plasmin inhibitor. Blood 1987; 69: 446-53.
- 31 Kimura S, Tamaki T, Aoki N. Acceleration of fibrinolysis by the N-terminal peptide of α2-plasmin inhibitor. Blood 1985; 66: 157-60.
- 32 Lee KN, Tae WC, Jackson KW, Kwon SH, McKee PA. Characterization of wild-type and mutant α2-antiplasmins: fibrinolysis enhancement by reactive site mutant. Blood 1999; 94: 164-71.
- 33 Sumi Y, Ichikawa Y, Nakamura Y, Miura O, Aoki N. Expression and characterization of pro α2-plasmin inhibitor. J Biochem (Tokyo) 1989; 106: 703-7.
- 34 Chung DH, Ohashi K, Watanabe M, Miyasaka N, Hirosawa S. Mannose trimming targets mutant α2-plasmin inhibitor for degradation by the proteasome. J Biol Chem 2000; 275: 4981-7.