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dc.contributor.authorBerber, Ergül
dc.contributor.authorÖzbil, Mehmet
dc.contributor.authorBrown, Christine
dc.contributor.authorBaşlar, Zafer
dc.contributor.authorÇağlayan, S. Hande
dc.contributor.authorLillicrap, David
dc.date.accessioned2019-07-04T13:35:52Z
dc.date.available2019-07-04T13:35:52Z
dc.date.issued2017en_US
dc.identifier.citationBerber, E., Ozbil, M., Brown, C., Baslar, Z., Caglayan, S. H., & Lillicrap, D. (2017). Functional characterisation of the type 1 von Willebrand disease candidate VWF gene variants: p. M771I, p. L881R and p. P1413L. Blood Transfusion, 15(6), 548-556. doi:10.2450/2016.0034-16en_US
dc.identifier.issn1723-2007
dc.identifier.urihttps://hdl.handle.net/20.500.12294/1557
dc.descriptionBerber, Ergül (Arel Author), Özbil, Mehmet (Arel Author)en_US
dc.description.abstractBackground. Abnormalities in the biosynthetic pathway or increased clearance of plasma von Willebrand factor (VWF) are likely to contribute to decreased plasma VWF levels in inherited type 1 von Willebrand disease (VWD). Recent studies demonstrated that 65% of type 1 VWD patients have candidate VWF mutations, the majority of which are missense variants. The purpose of this study was to explore the effects of three VWF missense mutations (p. M771I, p. L881R and p. P1413L) located in different functional domains of VWF, reported as candidate mutations in type 1 VWD patients in the course of the MCMDM-1VWD study. Materials and methods. The focus of these studies was on the intracellular biosynthetic processing and localisation of VWF in a heterologous cell system. Molecular dynamic simulation for p. M771I and p. P1413L was also performed to analyse the conformational effects of the changes. Results. As determined by immunofluorescence antibody staining and confocal microscopy of HEK293 cells, the intracellular localisation of recombinant VWF with the p. M771I variation was impaired. Transient transfection studies and phorbol myristate acetate stimulation in COS-7 cells revealed significant intracellular retention. In addition, major loss of VWF multimers was observed for only the p. M771I mutation. Molecular dynamic simulations on p. M771I mutant VWF revealed distinct structural rearrangements including a large deviation in the E' domain, and significant loss of beta-sheet secondary structure. Discussion. The pathogenic effects of candidate VWF gene mutations were explored in this study. In vitro expression studies in heterologous cell systems revealed impaired secretion of VWF and a dominant negative effect on the processing of the wild-type protein for only the p. M771I mutation and none of the mutations affected the regulated secretion.en_US
dc.language.isoengen_US
dc.publisherSIMTI Servizien_US
dc.relation.isversionof10.2450/2016.0034-16en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleFunctional characterisation of the type 1 von Willebrand disease candidate VWF gene variants: p. M771I, p. L881R and p. P1413Len_US
dc.typearticleen_US
dc.relation.journalBlood Transfusionen_US
dc.contributor.departmentFen-Edebiyat Fakültesi, Moleküler Biyoloji ve Genetik Bölümüen_US
dc.contributor.authorIDhttp://orcid.org/0000-0002-1465-7674en_US
dc.identifier.volume15en_US
dc.identifier.issue6en_US
dc.identifier.startpage548en_US
dc.identifier.endpage556en_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/107S320


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