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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1305-1310.
Prepublished online as a Blood First Edition Paper on October 16, 2003; DOI 10.1182/blood-2003-06-1796.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome
Masanori Matsumoto,
Koichi Kokame,
Kenji Soejima,
Masayoshi Miura,
Syuhei Hayashi,
Yasuhiko Fujii,
Asayuki Iwai,
Etsuro Ito,
Yoichiro Tsuji,
Mayuko Takeda-Shitaka,
Mitsuo Iwadate,
Hideaki Umeyama,
Hideo Yagi,
Hiromichi Ishizashi,
Fumiaki Banno,
Tomohiro Nakagaki,
Toshiyuki Miyata, and
Yoshihiro Fujimura
From the Departments of Blood Transfusion Medicine and Health Science, Nara Medical University, Kashihara, Japan; the National Cardiovascular Center Research Institute, Suita, Japan; the First Research Department, the Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan; the Department of Pediatrics, Toyama City Hospital, Toyama, Japan; the Department of Pediatrics, Fukui Red Cross Hospital, Fukui, Japan; the Department of Blood Transfusion Medicine, Yamaguchi University School of Medicine, Ube, Japan; the Department of Pediatrics, Kagawa Children's Hospital, Zentsuji, Japan; the Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan; the Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan; and the School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
We report here 7 new mutations in the ADAMTS13 gene responsible for Upshaw-Schulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura, by analyzing 5 Japanese families. There were 3 mutations that occurred at exon-intron boundaries: 414+1G>A at intron 4, 686+1G>A at intron 6, and 1244+2T>G at intron 10 (numbered from the A of the initiation Met codon), and we confirmed that 2 of these mutations produced aberrantly spliced messenger RNAs (mRNAs). The remaining 4 mutations were missense mutations: R193W, I673F, C908Y, and R1123C. In expression experiments using HeLa cells, all mutants showed no or a marginal secretion of ADAMTS13. Taken together with the findings in our recent report we determined the responsible mutations in a total of 7 Japanese patients with USS with a uniform clinical picture of severe neonatal hyperbilirubinemia, and in their family members, based on ADAMTS13 gene analysis. Of these patients, 2 were homozygotes and 5 were compound heterozygotes. The parents of one homozygote were related (cousins), while those of the other were not. Molecular models of the metalloprotease, fifth domain of thrombospondin 1 (Tsp1-5), and Tsp1-8 domains of ADAMTS13 suggest that the missense mutations could cause structural defects in the mutants.
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