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Von Willebrand factor propeptide missense mutations affect anterograde transport to Golgi resulting in ER accumulation
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  • Hamideh Yadegari,
  • Arijit Biswas,
  • Shariq Ahmed,
  • Arshi Naz,
  • Johannes Oldenburg
Hamideh Yadegari
University Hospital Bonn Institute for Experimental Hematology and Transfusion Medicine
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Arijit Biswas
Universitatsklinikum Bonn
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Shariq Ahmed
National Institute of Blood Disease & Bone Marrow Transplantation Karachi
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Arshi Naz
National Institute of Blood Disease & Bone Marrow Transplantation Karachi
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Johannes Oldenburg
University Hospital Bonn Institute for Experimental Hematology and Transfusion Medicine
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Abstract

Von Willebrand disease (VWD), the most prevalent congenital bleeding disorder, arises from a deficiency in von Willebrand factor (VWF), which has crucial roles in hemostasis. The present study investigated functional consequences and underlying pathomolecular mechanisms of several VWF propeptide (VWFpp) variants detected in our cohort of VWD patients for the first time. Transient expression experiments in HEK293T cells demonstrated that four out of the six investigated variants (p.Gly55Glu, p.Val86Glu, p.Trp191Arg, and p.Cys608Trp) severely impaired secretion. Their co-transfections with the wt partly corrected VWF secretion, displaying loss of large/intermediate multimers. Immunostaining of the transfected HEK293 cells illustrated the retention of the VWF variants in the endoplasmic reticulum (ER). Docking of the COP I and COP II cargo recruitment proteins, ADP-ribosylation factor 1 and Sec24, onto the N-terminal VWF model (D1D2D´D3) revealed that these variants occur at VWFpp putative interfaces, which can hinder VWF loading at the ER exit quality control. Furthermore, quantitative and automated morphometric exploration of the 3-dimensional immunofluorescence images showed changes in the number/size of the VWF storage organelles, Weibel-Palade body (WPB)-like vesicles. The result of this study highlighted the significance of the VWFpp variants on anterograde ER-Golgi trafficking of VWF as well as the biogenesis of WPB-like vesicles.

Peer review status:ACCEPTED

23 Sep 2020Submitted to Human Mutation
24 Sep 2020Submission Checks Completed
24 Sep 2020Assigned to Editor
02 Oct 2020Reviewer(s) Assigned
03 Nov 2020Review(s) Completed, Editorial Evaluation Pending
15 Nov 2020Editorial Decision: Revise Major
18 Feb 20211st Revision Received
23 Feb 2021Submission Checks Completed
23 Feb 2021Assigned to Editor
01 Mar 2021Reviewer(s) Assigned
19 Mar 2021Review(s) Completed, Editorial Evaluation Pending
02 Apr 2021Editorial Decision: Accept