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J. Biol. Chem., Vol. 279, Issue 29, 30896-30903, July 16, 2004

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Identification of Strain-specific Variants of Mouse Adamts13 Gene Encoding von Willebrand Factor-cleaving Protease^*

Fumiaki Banno, Kazuyoshi Kaminaka, Kenji Soejima, Koichi Kokame, and Toshiyuki Miyata¶

From the National Cardiovascular Center Research Institute, Osaka 565-8565, Japan and the First Research Department, The Chemo-Sero-Therapeutic Research Institute, Kumamoto 869-1298, Japan

Human ADAMTS13 was recently identified as a gene encoding von Willebrand factor-cleaving protease, hADAMTS13. Both congenital and acquired defects in this enzyme can cause thrombotic thrombocytopenic purpura. hADAMTS13 consists of 1,427 amino acid residues and is composed of multiple structural domains including thrombospondin type 1 motifs and CUB domains. To analyze the functional roles of these domains in vivo, we determined the cDNA sequence of the mouse ortholog, mADAMTS13. Unexpectedly, two forms of the mouse Adamts13 gene were isolated that differed in the insertion of an intracisternal A particle (IAP) retrotransposon including a premature stop codon. The IAP insertion was found in BALB/c, C3H/He, C57BL/6, and DBA/2 strains but not in the 129/Sv strain. The outbred ICR strain had either the IAP-free or IAP-inserted allele or both. IAP-free Adamts13 encoded mADAMTS13L, a protein of 1,426 amino acid residues with the same domain organization as hADAMTS13. In contrast, IAP-inserted Adamts13 encoded a C-terminally truncated enzyme, mADAMTS13S, that is comprised of only 1,037 amino acid residues and lacking the C-terminal two thrombospondin type 1 motifs and two CUB domains. Strain specificity was also confirmed by reverse transcription-PCR and Northern blot analyses. Both recombinant mADAMTS13L and mADAMTS13S exhibited von Willebrand factor cleaving activities in vitro. The natural variation in mouse ADAMTS13 should allow for the determination of hitherto unknown functions of its C-terminal domains in vivo.

Received for publication, December 26, 2003 , and in revised form, May 7, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AB071302, AB095445, and AB112362.

^* This work was supported in part by grants-in-aid from the Ministry of Health, Labor, and Welfare of Japan; from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; from the Japan Society for the Promotion of Science; and from the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Tel.: 81-6-6833-5012; Fax: 81-6-6835-1176; E-mail: miyata{at}ri.ncvc.go.jp.

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