Abstract |
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.
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Authors | 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 |
Journal | Blood advances
(Blood Adv)
Vol. 4
Issue 13
Pg. 2979-2990
(07 14 2020)
ISSN: 2473-9537 [Electronic] United States |
PMID | 32609846
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 by The American Society of Hematology. |
Chemical References |
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Topics |
- DNA Copy Number Variations
- Humans
- Weibel-Palade Bodies
- von Willebrand Disease, Type 1
- von Willebrand Diseases
(diagnosis, genetics)
- von Willebrand Factor
(genetics)
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