Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.
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.
Matsumoto
Masanori
M
Department of Blood Transfusion Medicine, Nara Medical University, Shijyo-cho 840, Kashihara city, Nara 634-8522, Japan.
Kokame
Koichi
K
Soejima
Kenji
K
Miura
Masayoshi
M
Hayashi
Syuhei
S
Fujii
Yasuhiko
Y
Iwai
Asayuki
A
Ito
Etsuro
E
Tsuji
Yoichiro
Y
Takeda-Shitaka
Mayuko
M
Iwadate
Mitsuo
M
Umeyama
Hideaki
H
Yagi
Hideo
H
Ishizashi
Hiromichi
H
Banno
Fumiaki
F
Nakagaki
Tomohiro
T
Miyata
Toshiyuki
T
Fujimura
Yoshihiro
Y
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
D019700:Thrombospondin 1; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human