ADAMTS13 activity and genetic mutations in Japan

Summary

Thrombotic thrombocytopenic purpura (TTP), a life threatening disease, can be induced by congenital or acquired deficiency of plasma metalloprotease ADAMTS13. Since the publication of the first genetic analysis in patients with congenital ADAMTS13 deficiency in 2001, more than 100 genetic defects in the ADAMTS13 gene have been reported worldwide. Genetic analysis in patients with ADAMTS13 deficiency has greatly contributed to the understanding of the etiology of TTP. A rapid and quantitative assay method for the plasma ADAMTS13 activity was developed recently in 2005 and opened a new area of TTP research – namely genetic research using a general population to evaluate age and gender differences of ADAMTS13 activity as well as phenotype – genotype correlations of genetic polymorphisms and estimation of a homozygote or a compound heterozygote ADAMTS13 deficiencies. The Japanese general population study included 3616 individuals with an age between 30 – 80 years confirming other studies that while ADAMTS13 activity decreased with age, VWF antigen increased and VWF antigen levels are lowest in blood group O indviduals, whereas ADAMTS13 activity levels were not associated with the AB0 blood group. 25 polymorphisms with a minor allele frequency of more than 0.01 were found, among them 6 missense mutations and 19 synonymous mutations, except P475S missense polymorphisms that was only idenitified in an East Asian population, characterized by reduced ADAMTS13 activity. Prevalence of congenital ADAMTS13 deficiency in the Japanese population was estimated about one individual in 1.1 × 10⁶ to be homozygote or compound heterozygote for ADAMTS13 deficiency. So far more than 40 mutations in Japanese congenital TTP patients were found, but R193W, Q449*, C754Afs*24 (c.2259delA) and C908Y were identified in more than four patients suggesting the precipitaion of these mutations in the Japanese population.

Zusammenfassung

Die thrombotisch-thrombozytopenische Purpura (TTP), eine lebensbedrohliche Erkrankung, kann durch kongenitalen oder erworbenen Mangel an Metalloprotease ADAMTS13 im Plasma ausgelöst werden. Seit 2001 die erste genetische Analyse bei Patienten mit kongenitalem ADAMTS13-Mangel publiziert wurde, sind weltweit mehr als 100 Gendefekte im ADAMTS13-Gen beschrieben worden. Die Genanalyse bei Patienten mit ADAMTS13- Mangel hat viel zum Verständnis der Ätiologie von TTP beigetragen. Ein schnelles und quantitatives Testverfahren wurde 2005 für die Aktivität von ADAMTS13 im Plasma entwickelt und damit ein neues TTP-Forschungsgebiet begründet – und zwar die genetische Erforschung alters- und geschlechtsbedingter Unterschiede bei der ADAMTS13-Aktivität in der Allgemeinbevölkerung, von Zusammenhängen zwischen Phäno- und Genotyp bei genetischen Polymorphismen sowie der Bewertung des homozygoten bzw. kombinierten heterozygoten ADAMTS13-Mangels. In der japanischen Bevölkerungsstudie an 3616 Personen im Alter von 30 bis 80 Jahren wurden die Ergebnisse anderer Studien bestätigt, dass zwar die ADAMTS13- Aktivität mit dem Alter abnimmt, das VWF-Antigen jedoch ansteigt, und dass die Konzentration des VWFAntigens bei Personen mit Blutgruppe 0 am niedrigsten ist, während das ADAMTS13-Aktivitätsniveau keinen Zusammenhang mit der Blutgruppe AB0 aufwies. Es wurden 25 Polymorphismen mit einer Allelfrequenz über 0,01 gefunden, darunter 6 Missense-Mutationen und 19 synonyme Mutationen, außer dem P475S-Missense-Polymorphismus, der ausschließlich in einer ostasiatischen Population identifiziert wurde und durch reduzierte ADAMTS13- Aktivität gekennzeichnet ist. Bei der Prävalenz des kongenitalen ADAMTS13- Mangels in der japanischen Bevölkerung schätzt man, dass 1 von 1,1 × 10⁶ homozygot oder kombiniert heterozygot für einen ADAMTS13-Mangel ist. Bislang wurden mehr als 40 Mutationen bei japanischen Patienten mit kongenitaler TTP entdeckt; jedoch fand man R193W, Q449*, C754Afs*24 (c.2259delA) und C908Y bei mehr als vier Patienten und nimmt daher an, dass diese Mutationen gehäuft in der japanischen Bevölkerung vorkommen.

Keywords

ADAMTS13 - genetic mutation - thrombotic thrombocytopenic purpura

Schlüsselwörter

ADAMTS13 - Mutation - thrombotisch-thrombozytopenische Purpura - TTP

• References

• 1 Soejima K, Mimura N, Hirashima M. et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease?. J Biochem 2001; 130: 475-480.
• 2 Zheng X, Chung D, Takayama TK. et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-41063.
• 3 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
• 4 Uemura M, Tatsumi K, Matsumoto M. et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005; 106: 922-924.
• 5 Zhou W, Inada M, Lee TP. et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005; 85: 780-788.
• 6 Soejima K, Nakamura H, Hirashima M. et al. Analysis on the molecular species and concentration of circulating ADAMTS13 in Blood. J Biochem 2006; 139: 147-154.
• 7 Rieger M, Ferrari S, Kremer JAHovinga. et al. Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA). Thromb Haemost 2006; 95: 212-220.
• 8 Feys HB, Anderson PJ, Vanhoorelbeke K. et al. Multi-step binding of ADAMTS-13 to von Willebrand factor. J Thromb Haemost 2009; 07: 2088-2095.
• 9 Zanardelli S, Chion AC, Groot E. et al. A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF. Blood 2009; 114: 2819-2828.
• 10 Banno F, Chauhan AK, Kokame K. et al. The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 2009; 113: 5323-5329.
• 11 Furlan M, Robles R, Morselli B. et al. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 1999; 81: 8-13.
• 12 Shin Y, Akiyama M, Kokame K. et al. Binding of von Willebrand factor cleaving protease ADAMTS13 to Lys-plasmin(ogen). J Biochem 2012; 152: 251-258.
• 13 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112: 11-18.
• 14 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
• 15 Furlan M, Robles R, Solenthaler M, Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998; 91: 2839-2846.
• 16 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-1594.
• 17 Shim K, Anderson PJ, Tuley EA. et al. Platelet- VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008; 111: 651-657.
• 18 Cao W, Krishnaswamy S, Camire RM. et al. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc Natl Acad Sci USA 2008; 105: 7416-7421.
• 19 Zhou YF, Eng ET, Nishida N. et al. A pH-regulated dimeric bouquet in the structure of von Willebrand factor. Embo J 2011; 30: 4098-4111.
• 20 Zhang Q, Zhou YF, Zhang CZ. et al. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci USA 2009; 106: 9226-9231.
• 21 Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood 1994; 83: 2171-2179.
• 22 Zhang X, Halvorsen K, Zhang CZ. et al. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 324: 1330-1334.
• 23 Dent JA, Berkowitz SD, Ware J. et al. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6306-6310.
• 24 Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129: 93-100.
• 25 Kato S, Matsumoto M, Matsuyama T. et al. Y. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion 2006; 46: 1444-1452.
• 26 Kokame K, Matsumoto M, Fujimura Y, Miyata T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 2004; 103: 607-612.
• 27 Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2004; 407-423.
• 28 Miyata T, Kokame K, Banno F. Measurement of ADAMTS-13 activity and inhibitors. Curr Opin Hematol 2005; 12: 384-389.
• 29 Peyvandi F, Palla R, Lotta LA. et al. ADAMTS-13 assays in thrombotic thrombocytopenic purpura. J Thromb Haemost 2010; 08: 631-640.
• 30 Froehlich-Zahnd R, George JN, Vesely SK. et al. Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura. Haematologica 2012; 97: 297-303.
• 31 Kokame K, Sakata T, Kokubo Y, Miyata T. von Willebrand factor-to-ADAMTS13 ratio increases with age in a Japanese population. J Thromb Haemost 2011; 09: 1426-1428.
• 32 Gill JC, Endres-Brooks J, Bauer PJ. et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
• 33 Chion CK, Doggen CJ, Crawley JT. et al. ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. Blood 2007; 109: 1998-2000.
• 34 Matsui T, Titani K, Mizuochi T. Structures of the asparagine-linked oligosaccharide chains of human von Willebrand factor. Occurrence of blood group A, B, and H(O) structures. J Biol Chem 1992; 267: 8723-8731.
• 35 Hiura H, Matsui T, Matsumoto M. et al. Proteolytic fragmentation and sugar chains of plasma ADAMTS13 purified by a conformation-dependent monoclonal antibody. J Biochem 2010; 148: 403-411.
• 36 Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin Hematol 2004; 41: 34-40.
• 37 Lotta LA, Garagiola I, Palla R. et al. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat 2010; 31: 11-19.
• 38 Kaikita K, Soejima K, Matsukawa M. et al. Reduced von Willebrand factor-cleaving protease (ADAMTS13) activity in acute myocardial infarction. J Thromb Haemost 2006; 04: 2490-2493.
• 39 Miura M, Kaikita K, Matsukawa M. et al. Prognostic value of plasma von Willebrand factorcleaving protease (ADAMTS13) antigen levels in patients with coronary artery disease. Thromb Haemost 2010; 103: 623-629.
• 40 Andersson HM, Siegerink B, Luken BM. et al. High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women. Blood 2012; 119: 1555-1560.
• 41 Akiyama M, Takeda S, Kokame K. et al. Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor. Proc Natl Acad Sci USA 2009; 106: 19274-19279.
• 42 Kokame K, Kokubo Y, Miyata T. Polymorphisms and mutations of ADAMTS13 in the Japanese population and estimation of the number of patients with Upshaw-Schulman syndrome. J Thromb Haemost 2011; 09: 1654-1656.
• 43 Akiyama M, Kokame K, Miyata T. ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea lability in vitro. J Thromb Haemost 2008; 06: 1830-1832.
• 44 Akiyama M, Nakayama D, Takeda S. et al. Crystal structure and enzymatic activity of an ADAMTS13 mutant with the East Asian-specific P475S polymorphism. J Thromb Haemost. 2013 in press.
• 45 Plaimauer B, Fuhrmann J, Mohr G. et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood 2006; 107: 118-125.
• 46 Fujimura Y, Matsumoto M, Isonishi A. et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011; 09 (Suppl. 01) 283-301.
• 47 Matsumoto M, Kokame K, Soejima K. et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 2004; 103: 1305-1310.
• 48 Schneppenheim R, Kremer JAHovinga, Becker T. et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost 2006; 96: 3-6.
• 49 Lotta LA, Wu HM, Mackie IJ. et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 2012; 120: 440-448.