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Blood, 1 January 2006, Vol. 107, No. 1, pp. 118-125. Prepublished online as a Blood First Edition Paper on September 13, 2005; DOI 10.1182/blood-2005-06-2482. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-06-2482v1 107/1/118    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Plaimauer, B. Articles by Scheiflinger, F. Search for Related Content PubMed PubMed Citation Articles by Plaimauer, B. Articles by Scheiflinger, F. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation Barbara Plaimauer, Jakob Fuhrmann, Gabriele Mohr, Waltraud Wernhart, Katharina Bruno, Silvia Ferrari, Christian Konetschny, Gerhard Antoine, Manfred Rieger, and Friedrich Scheiflinger From the Baxter Bioscience, Department of Discovery Research, Vienna, Austria. Sequence analysis of the ADAMTS13 locus of 2 patients with hereditary thrombotic thrombocytopenic purpura (TTP) revealed the homozygous presence of 4 single nucleotide polymorphisms (SNPs) (R7W, Q448E, P618A, A732V) and a rare missense mutation (R1336W). Analysis of the individual effect of any amino acid exchanges showed that several sequence variations can interact with each other, thereby altering the phenotype of ADAMTS13 deficiency. Introduction of polymorphisms R7W, Q448E, and A732V had no or only minor effects on ADAMTS13 secretion. In contrast, P618A, R1336W, and the A732V-P618A combination strongly reduced ADAMTS13-specific activity and antigen levels. Surprisingly, R7W and Q448E were positive modifiers of ADAMTS13 secretion in the context of P618A and A732V but neither could rescue the severely reduced specific activity conferred by P618A. However, in the context of R1336W, polymorphisms R7W and Q448E enhanced the detrimental effect of the missense mutation and led to undetectable enzyme activity. We show that dependent on the sequence context, the same polymorphisms might be either positive or negative modifiers of gene expression. Our results might therefore be widely relevant to understanding the influence of polymorphisms on the phenotypic expression of complex diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Raef, E. Y Baitei, M. Zou, and Y. Shi Genotype-phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism. Eur. J. Endocrinol., April 1, 2008; 158(4): 577 - 582. [Abstract] [Full Text] [PDF] D. Shang, X. W. Zheng, M. Niiya, and X. L. Zheng Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts Blood, October 1, 2006; 108(7): 2207 - 2215. [Abstract] [Full Text] [PDF]

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