Absence of Pro475Ser polymorphism in ADAMTS‐13 in Caucasians

Bongers, T.N.; Maat, Moniek P.M. de; Dippel, Diederik W.J.; Uitterlinden, André G.; Leebeek, Frank W.G.

doi:10.1111/j.1538-7836.2005.01239.x

Cited by 20 publications

(14 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 Plaimauer et al expressed several constructs of recombinant For personal use only. on May 9, 2018. by guest www.bloodjournal.org From ADAMTS13 and observed that both the A732V and P618A polymorphisms reduced secretion (60% and 27%, respectively) and activity (72% and 14%, respectively) in comparison with WT.…”

Section: Discussionmentioning

confidence: 99%

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Feng

Eyler

Zhang

et al. 2013

Blood

View full text Add to dashboard Cite

• Reduction in ADAMTS13 function and complement dysregulation coexist in a significant number of patients with aHUS.• Variations in the ADAMTS13 gene (polymorphisms and rare variants) are partly responsible for the reduced ADAMTS13 function in aHUS.Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants-A747V, V832M, and R1096H-were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients. (Blood.

show abstract

Section: Discussionmentioning

confidence: 99%

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Feng

Eyler

Zhang

et al. 2013

Blood

View full text Add to dashboard Cite

show abstract

“…A number of nonsynonymous mutations and polymorphisms of ADAMTS13 have been identified [4,5]. Among them, the P475S (c.1423C > T) polymorphism is noteworthy.The allele frequency of ADAMTS13 P475S was 5.1% in Japanese subjects [6], 4.0% in Koreans [7], and 1.5% in Chinese [8], but absent in Caucasians [9]. The recombinant P475S mutant was normally secreted from cultured cells but showed greatly reduced enzymatic activity (10%) in the VWFmultimer assay [6].…”

mentioning

confidence: 99%

“…However, in these studies only AA-induced PA was used to explore aspirin resistance. No direct measure of platelet TxA 2 , considered a prerequisite to analyze the rate of COX1 and eventually aspirin resistance, was provided [9]. Here, we undertook a prospective study to further evaluate the role of compliance on aspirin resistance intended as residual platelet reactivity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea labilityin vitro

Akiyama

Kokame

Miyata

2008

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

To cite this article: Akiyama M, Kokame K, Miyata T. ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea lability in vitro. J Thromb Haemost 2008; 6: 1830-2.von Willebrand factor (VWF) is a plasma glycoprotein synthesized primarily in vascular endothelial cells and megakaryocytes [1]. VWF is released into plasma as ultra-large multimeric forms that are highly active in platelet aggregation. A plasma metalloprotease ADAMTS13 specifically cleaves the Tyr 1605 -Met 1606 peptidyl bond within the A2 domain of VWF [2]. Deficiency of the ADAMTS13 enzymatic activity, caused by genetic mutations or acquired autoantibodies against ADAMTS13, results in the accumulation of ultra-large VWF multimers in plasma that lead to the hyper-aggregation of platelets. This prothrombotic condition can cause thrombotic thrombocytopenic purpura (TTP) [3]. A number of nonsynonymous mutations and polymorphisms of ADAMTS13 have been identified [4,5]. Among them, the P475S (c.1423C > T) polymorphism is noteworthy.The allele frequency of ADAMTS13 P475S was 5.1% in Japanese subjects [6], 4.0% in Koreans [7], and 1.5% in Chinese [8], but absent in Caucasians [9]. The recombinant P475S mutant was normally secreted from cultured cells but showed greatly reduced enzymatic activity (10%) in the VWFmultimer assay [6]. Recently, we have developed a quantitative ADAMTS13 activity assay using a synthetic fluorogenic substrate FRETS-VWF73 [10] and it is now widely utilized [11][12][13][14]. The assay can be performed in the absence of urea that is required for the VWF-multimer assay. In this study, we evaluated the activity of the P475S mutant using FRETS-VWF73 and found that the mutant exhibited the more profound loss of activity than the wild-type in the presence of urea.We have prepared four forms of recombinant ADAMTS13 using a transient expression system of HeLa cells: the fulllength form (Met ) with the wild-type sequence (MDTCS) or with the P475S polymorphism (MDTCS-P475S). FL and FL-P475S were tagged by the C-terminal FLAG sequence. MDTCS and MDTCS-P475S were tagged by the C-terminal 6xHis sequence. The culture media of cells expressing FL and FL-P475S were collected and concentrated 5-fold by centrifugal filtration (Ultrafree-MC; Millippore, Billerica, MA, USA). The media of cells expressing MDTCS and MDTCS-P475S were collected, and the recombinant proteins were purified by the Ni-NTA column chromatography. The relative amounts of the recombinant proteins were adjusted by their band intensities of Western blotting analysis using anti-FLAG or anti-6xHis antibodies, within the linear detection range. Enzymatic activity of each protein was measured by the FRETS-VWF73 assay [10] in the absence or presence of urea.First, we compared the enzymatic activities between FL and FL-P475S in the absence of urea, and found that FL-P475S showed 71 ± 3.6% (n = 3) activity of FL. We previously reported that FL-P475S showed only approximately 10% activity of FL in the VWF-multimer assay [6]. This paradoxical observation led us to further stud...

show abstract

“…Among them, the proline (Pro) to serine (Ser) polymorphism in codon 475 of the ADAMTS13 gene (Pro475Ser), caused by a base substitution of C1423 to T in exon 12 (C1423T) which was found to impair ADAMTS-13 activity in vitro , has been reported to be common in the Japanese population, and suggested that the importance of TTP or thrombosis-related gene in Japanese 10. However, subsequent studies carried out in the Chinese population13 or Caucasians14 did not show positive correlation of C1423T with thrombotic disorders. The allele frequency of C1423T was only 1.5% in the Chinese population, and the heterozygous genotype was not associated with an increased risk of acute ischemic stroke and acute myocardial infarction 13.…”

Section: Introductionmentioning

confidence: 99%

Frequency of Pro475Ser Polymorphism of ADAMTS13 Gene and Its Association with ADAMTS-13 Activity in the Korean Population

et al. 2008

View full text Add to dashboard Cite

PurposeThe in vitro study suggested that proline to serine polymorphism in codon 475 (C1423T) of the A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats-13 (ADAMTS-13) gene is related to reduced activity of ADAMTS-13. In this study, the frequency of the Pro475Ser polymorphism in Koreans was studied and plasma ADAMTS-13 activity was measured to find out whether this polymorphism contributes to decreased ADAMTS-13 activity in Koreans.Patients and MethodsThe frequency of the C1423T allele of the ADAMTS13 gene was studied along with measuring plasma ADAMTS-13 activity in 250 healthy Korean individuals.ResultsThe allele frequency of C1423T polymorphism was 4%, and the median activity of CT type was 107 (69 - 143)%, which was lower than in controls with the CC genotype [118 (48 - 197)%, (p = 0.021)].ConclusionTherefore, the Pro475Ser polymorphism seems to be popular in the Korean population, and attenuates ADAMTS-13 plasma activity.

show abstract

Absence of Pro475Ser polymorphism in ADAMTS‐13 in Caucasians

Abstract: To cite this article: Bongers TN, de Maat MPM, Dippel DWJ, Uitterlinden AG, Leebeek FWG. Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians. J Thromb Haemost 2005; 3: 805.

Cited by 20 publications

References 4 publications

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea labilityin vitro

Frequency of Pro475Ser Polymorphism of ADAMTS13 Gene and Its Association with ADAMTS-13 Activity in the Korean Population

Contact Info

Product

Resources

About