Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura.
Congenital thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) is associated with an inherited von Willebrand factor-cleaving protease (ADAMTS13 [a disintegrin and metalloprotease with thrombospondin type I domains 13]) deficiency. In this study, we identified novel mutations in the ADAMTS13 gene in a patient with TTP. The patient was a 51-year-old Japanese male who exhibited TTP symptoms at frequent intervals. The ADAMTS13 activity during acute episodes was less than 3% that of normal. The enzyme activities of the patient's father and mother were both 46%, and both parents were asymptomatic. Genetic analysis revealed that the patient was a compound heterozygote for 2 mutations. One mutation was a missense mutation in the metalloprotease domain (A250V, exon 7), and the other was a guanine to adenine substitution at the 5' end of intron 3 (intron 3 G-->A). In vitro expression studies revealed that the A250V mutation markedly reduced ADAMTS13 activity and the intron 3 G-->A mutation caused abnormal mRNA synthesis.
Uchida
Toshihiro
T
New Product Laboratories II, Daiichi Pharmaceutical, Tokyo, Japan.
Wada
Hideo
H
Mizutani
Minoru
M
Iwashita
Miho
M
Ishihara
Hiroaki
H
Shibano
Toshiro
T
Suzuki
Misako
M
Matsubara
Yumiko
Y
Soejima
Kenji
K
Matsumoto
Masanori
M
Fujimura
Yoshihiro
Y
Ikeda
Yasuo
Y
Murata
Mitsuru
M
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000225:Adenine / Q000737:chemistry; D005091:Exons; D006147:Guanine / Q000737:chemistry; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008297:Male; D008666:Metalloendopeptidases / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry
D012333:RNA, Messenger; D011994:Recombinant Proteins; D006147:Guanine; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D000225:Adenine