NDLI: In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura

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In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura

Content Provider	Scilit
Author	Donadelli, Roberta Banterla, Federica Galbusera, Miriam Capoferri, Cristina Bucchioni, Sara Gastoldi, Sara Nosari, Silvia Monteferrante, Giuseppe Ruggeri, Zaverio M. Bresin, Elena Scheiflinger, Friedrich Rossi, Edoardo Martinez, Constantino Coppo, Rosanna Remuzzi, Giuseppe Noris, Marina
Copyright Year	2006
Description	Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13.We investigated the spectrum of ADAMTS13 gene mutations in patients with TTP and congenital ADAMTS13 deficiency to establish the consequences on ADAMTS13 processing and activity. We describe five missense (V88M, G1239V, R1060W, R1123C and R1219W), 1 nonsense (W1016Stop) and 1 insertion (82_83insT) mutations. In two patients no mutation was identified despite undetectable protease activity. Expression in HEK293 mammalian cells (V88M, G1239V, R1123C and R1219W) documented that three missense mutants were not secreted, whereas theV88M was secreted at low levels and with reduced activity. We also provide evidence that impaired secretion of ADAMTS13 mutants observed in vitro translates into severely reduced ADAMTS13 antigen levels in patients in vivo. To evaluate whether the small amounts of mutant protease present in the circulation of patients had VWF cleaving activity, WT and mutant rADAMTS13 were stably expressed in Drosophila S2 cells under the influence of the Drosophila BiP protein signal sequence, which allows protein secretion. Drosophila expression system showed a 40–60% protease activity in the mutants. Several single nucleotide polymorphisms (SNPs) within exons and intron boundaries were found in patients, suggesting that the interplay of SNPs could at least in part account for ADAMTS13 functional abnormalities in patients without mutations. In conclusion, defective secretion and impaired activity of the mutants concur to determine an almost complete deficiency of ADAMTS13 activity in patients with a homozygous or two heterozygous ADAMTS13 mutations.
Related Links	http://www.thieme-connect.de/products/ejournals/pdf/10.1160/TH06-05-0236.pdf
Ending Page	464
Page Count	11
Starting Page	454
ISSN	2567689X
DOI	10.1160/th06-05-0236
Journal	Thrombosis and Haemostasis
Issue Number	10
Volume Number	96
Language	English
Publisher	Georg Thieme Verlag KG
Publisher Date	2006-01-01
Access Restriction	Open
Subject Keyword	Journal: Thrombosis and Haemostasis Mutations in Patients Impaired Secretion Protease Activity Deficiency of Adamts13
Content Type	Text
Resource Type	Article
Subject	Hematology

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Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

von Willebrand factor-cleaving protease activity in congenital thrombotic thrombocytopenic purpura

In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS 13 in thrombotic thrombocytopenic purpura

Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura

ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura

Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies

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FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients

In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura

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