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Characterization of...
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Cartwright, AshleyEngland
(author)
Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms
- Article/chapterEnglish2020
Publisher, publication year, extent ...
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2020-07-01
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Elsevier BV,2020
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11
Numbers
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LIBRIS-ID:oai:researchportal.hkr.se/admin:publications/44845f5c-4190-412e-a0fe-2dc92cf7296c
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oai:researchportal.hkr.se/admin:publications/44845f5c-4190-412e-a0fe-2dc92cf7296cURI
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https://doi.org/10.1182/bloodadvances.2018027813DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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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Webster, Simon JEngland
(author)
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de Jong, AnnikaNetherlands,Nederländerna
(author)
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Dirven, Richard JNetherlands,Nederländerna
(author)
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Bloomer, Lisa D SEngland
(author)
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Al-Buhairan, Ahlam MEngland
(author)
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Budde, UlrichGermany,Tyskland
(author)
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Halldén, ChristerBiomedicin(Swepub:hkr)9f106859-211e-4907-96a5-55f48cf6d357
(author)
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Habart, DavidCzech Republic,Tjeckien
(author)
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Goudemand, JennyFrance,Frankrike
(author)
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Peake, Ian REngland
(author)
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Eikenboom, Jeroen C JNetherlands,Nederländerna
(author)
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Goodeve, Anne CEngland
(author)
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Hampshire, Daniel JEngland
(author)
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EnglandNetherlands
(creator_code:org_t)
Related titles
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In:Blood Advances: Elsevier BV4:13, s. 2979-29902473-95292473-9537
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Cartwright, Ashl ...
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Webster, Simon J
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de Jong, Annika
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Dirven, Richard ...
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Budde, Ulrich
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Halldén, Christe ...
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Habart, David
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Goudemand, Jenny
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Peake, Ian R
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Goodeve, Anne C
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Blood Advances
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Kristianstad University College