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Blood, 1 August 2007, Vol. 110, No. 3, pp. 886-893.
Prepublished online as a Blood First Edition Paper on April 10, 2007June 4, 2007; DOI 10.1182/blood-2007-01-070953.
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Submitted January 30, 2007
Accepted April 5, 2007
An IAP retrotransposon in the mouse ADAMTS13 gene creates ADAMTS13 variant proteins that are less effective in
cleaving von Willebrand factor multimers
Wenhua Zhou, Eric E Bouhassira, and Han-Mou Tsai*
Division of Hematology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, United States
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States
* Corresponding author; email: htsai{at}montefiore.org.
Severe deficiency of ADAMTS13, a von Willebrand factor cleaving metalloprotease, causes thrombotic thrombocytopenic purpura. When analyzed with VWF multimers, but not with an abbreviated VWF peptide (VWF73) as the substrate, the plasma ADAMTS13 activity levels of mouse strains segregated in a high and a low group that differed by approximately 10 folds. Low ADAMTS13 activity was detected in mice containing two alleles of IAP-type retrotransposon sequence in the ADAMTS13 gene. Molecular cloning of mouse ADAMTS13 identified two truncated variants (IAP-a and IAP-b) in the low activity mice. Both the IAP variants lacked the two carboxyl terminus thrombospondin type 1 repeat (TSR) and CUB domains of full-length ADAMTS13. The IAP-b variant also had splicing abnormalities affecting the spacer domain sequence and had miniscule enzymatic activity. Compared to full-length ADAMTS13, the IAP-a variant was approximately one ninth as active in cleaving VWF multimers but was only slightly less active in cleaving VWF73 peptide. Recombinant human ADAMTS13 was also less effective in cleaving VWF multimers than VWF73 when the C-terminal TSR sequence was deleted. In summary, the carboxyl terminus TSR sequence is important for cleaving VWF multimers. Assay results should be interpreted with caution when peptide substrates are used for analysis of variant ADAMTS13 proteins.
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