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Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms
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2020 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 4, no 13, p. 2979-2990Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2020. Vol. 4, no 13, p. 2979-2990
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Biomedical Laboratory Science/Technology
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URN: urn:nbn:se:hkr:diva-20857DOI: 10.1182/bloodadvances.2018027813PubMedID: 32609846OAI: oai:DiVA.org:hkr-20857DiVA, id: diva2:1451703
Available from: 2020-07-03 Created: 2020-07-03 Last updated: 2020-12-15Bibliographically approved

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Halldén, Christer
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Avdelningen för NaturvetenskapForskningsmiljön Biomedicin
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CiteExportLink to record
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Citation style
  • apa
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