Published online 30 December 2008
Haematologica, Vol 94, Issue 2, 289-293 doi:10.3324/haematol.13524
Copyright © 2009 by Ferrata Storti Foundation
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Thrombotic Thrombocytopenic Purpura

The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura

Roberta Palla1, Silvia Lavoretano1, Rossana Lombardi1, Isabella Garagiola1, Mehran Karimi2, Abdolreza Afrasiabi2, Mani Ramzi2, Raimondo De Cristofaro3, Flora Peyvandi1

1 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
2 Hematology and Thrombosis Unit, Haematology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
3 Haemostasis Research Centre, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy

Correspondence: Flora Peyvandi, MD, PhD, 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, Via Pace 9, 20122 Milan, Italy., E-mail:flora.peyvandi{at}unimi.it

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.

Key words: ADAMTS13, thrombotic thrombocytopenic purpura, TSP-1 repeat, deletion, mutation.


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M. Galbusera, M. Noris, and G. Remuzzi
Inherited thrombotic thrombocytopenic purpura
Haematologica, February 1, 2009; 94(2): 166 - 170.
[Full Text] [PDF]