The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura.
The inherited deficiency of ADAMTS13 is usually associated with severe forms of thrombotic thrombocytopenic purpura. Among the mutations identified in the ADAMTS13 gene, none have been described on the TSP1-6 repeat domain. We investigated an Iranian family with a history of chronic recurrent thrombotic thrombocytopenic purpura, severe ADAMTS13 deficiency and a heterogeneous pattern of clinical symptoms among affected members. Genetic analysis revealed a homozygous deletion of nucleotides 2930-2935 (GTGCCC) in exon 23 of ADAMTS13, leading to the replacement of Cys977 by a Trp and the deletion of Ala978 and Arg979 in the TSP1-6 repeat domain. To explore the mechanism of ADAMTS13 deficiency, in vitro expression studies were performed. Western blotting, pulse-chase labeling and immunofluorescence studies demonstrated a secretion pathway defect of the mutant protein, with no intracellular accumulation. This finding is consistent with the severe ADAMTS13 deficiency but does not explain the heterogeneous clinical picture of the 3 siblings carrying the same mutation.
Palla
Roberta
R
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, University of Milan, Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy.
Lavoretano
Silvia
S
Lombardi
Rossana
R
Garagiola
Isabella
I
Karimi
Mehran
M
Afrasiabi
Abdolreza
A
Ramzi
Mani
M
De Cristofaro
Raimondo
R
Peyvandi
Flora
F
D051722:ADAM Proteins / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000328:Adult; D005192:Family Health; D006801:Humans; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D055815:Young Adult
D050505:Mutant Proteins; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human