Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Ashley Cartwright, Simon J Webster, Annika de Jong, Richard J Dirven, Lisa D S Bloomer, Ahlam M Al-Buhairan, Ulrich Budde, Christer Halldén, David Habart, Jenny Goudemand, Ian R Peake, Jeroen C J Eikenboom, Anne C Goodeve, Daniel J Hampshire

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8 Citations (Scopus)


Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion.

Original languageEnglish
Pages (from-to)2979-2990
Number of pages11
JournalBlood Advances
Issue number13
Publication statusPublished - 2020

Swedish Standard Keywords

  • Biomedical Laboratory Science/Technology (30402)


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