title: The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura.
abstract: 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.
authors.affiliation: 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.
authors.forename: Roberta
authors.initials: R
authors.lastname: Palla
authors.forename: Silvia
authors.initials: S
authors.lastname: Lavoretano
authors.forename: Rossana
authors.initials: R
authors.lastname: Lombardi
authors.forename: Isabella
authors.initials: I
authors.lastname: Garagiola
authors.forename: Mehran
authors.initials: M
authors.lastname: Karimi
authors.forename: Abdolreza
authors.initials: A
authors.lastname: Afrasiabi
authors.forename: Mani
authors.initials: M
authors.lastname: Ramzi
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: 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
chemical_list: D050505:Mutant Proteins; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human