Hamostaseologie 2013; 33(02): 131-137
DOI: 10.5482/HAMO-12-11-0017
Review
Schattauer GmbH

ADAMTS13 activity and genetic mutations in Japan

ADAMTS13-Aktivität und Mutationen in Japan
T. Miyata
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
,
K. Kokame
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
,
M. Matsumoto
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
2   Department of Blood Transfusion Medicine, Nara Medical University, Japan
,
Y. Fujimura
1   Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
2   Department of Blood Transfusion Medicine, Nara Medical University, Japan
› Author Affiliations
This work was supported in part by grantsin-aid from the Ministry of Health, Labor, Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Takeda Science Foundation.
Further Information

Publication History

received: 12 November 2012

accepted in revised form: 13 March 2013

Publication Date:
05 February 2018 (online)

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.

 
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