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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.
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Submitted June 22, 2005
Accepted August 19, 2005
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*
Department of Discovery Research, Baxter BioScience, Vienna, Austria
* Corresponding author; email: scheiff{at}baxter.com.
Sequence analysis of the ADAMTS13 locus of two hereditary thrombotic thrombocytopenic purpura (TTP) patients revealed the homozygous presence of four 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 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.
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