z-logo
Premium
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.

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here