title: Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.
abstract: 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.
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Shijyo-cho 840, Kashihara city, Nara 634-8522, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Kenji
authors.initials: K
authors.lastname: Soejima
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miura
authors.forename: Syuhei
authors.initials: S
authors.lastname: Hayashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Fujii
authors.forename: Asayuki
authors.initials: A
authors.lastname: Iwai
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takeda-Shitaka
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwadate
authors.forename: Hideaki
authors.initials: H
authors.lastname: Umeyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ishizashi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Banno
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakagaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
mesh_terms: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000328:Adult; D017398:Alternative Splicing; D000743:Anemia, Hemolytic / Q000235:genetics*; D005091:Exons; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D007564:Japan; D007567:Jaundice, Neonatal / Q000235:genetics; D008297:Male; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D013921:Thrombocytopenia / Q000235:genetics*; D019700:Thrombospondin 1 / Q000737:chemistry
chemical_list: D019700:Thrombospondin 1; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human