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The p.R1819_C1948delinsS mutation makes von Willebrand factor ADAMTS13‐resistant and reduces its collagen‐binding capacity
Author(s) -
Daidone Viviana,
Saga Giorgia,
Barbon Giovanni,
Pontara Elena,
Cattini Maria G.,
Morpurgo Margherita,
Zanotti Giuseppe,
Casonato Alessandra
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13472
Subject(s) - von willebrand factor , adamts , thrombospondin , adamts13 , von willebrand disease , disintegrin , platelet , chemistry , metalloproteinase , mutation , microbiology and biotechnology , binding domain , binding site , matrix metalloproteinase , medicine , biochemistry , biology , gene
Summary This report concerns abnormal ADAMTS 13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and collagen interactions coinciding with the p.R1819_C1948delinsS von Willebrand factor ( VWF ) mutation associated with the deletion of the C‐terminus of the A3 domain (amino acids 1819–1947) in a patient with a history of bleeding. The von Willebrand disease ( VWD ) phenotype of the patient featured low plasma and platelet VWF , multimers with smears extending over the highest normal oligomers in plasma, but not platelets, and an impaired collagen‐binding capacity. In vitro full‐length p.R1819_C1948delinsS VWF expression showed impaired VWF release, increased cellular content with normally‐multimerized VWF and impaired collagen binding. The recombinant p.R1819_C1948delinsS VWF fragment, extending from domains A2 to B3 (p.R1819_C1948delinsS A2‐B3 VWF ), was completely resistant to proteolysis by ADAMTS 13 in the presence of 1·5 mol/l urea, unlike its normal counterpart. The defect stems from impaired ADAMTS 13 binding to p.R1819_C1948delinsS A2‐B3, analysed under static conditions. Partial deletion of the C‐terminus of the A3 domain thus makes VWF resistant to ADAMTS 13, interfering with ADAMTS 13 binding to VWF , and impairing the collagen‐binding capacity of VWF . The p.R1819_C1948delinsS mutation has both haemorrhagic features (defective collagen binding, reduced VWF levels) and prothrombotic ( ADAMTS 13 resistance) features, and the latter probably mitigate the patient's bleeding symptoms.