PMID- 25103891
OWN - NLM
STAT- MEDLINE
DCOM- 20150311
LR  - 20181202
IS  - 1365-2141 (Electronic)
IS  - 0007-1048 (Linking)
VI  - 167
IP  - 4
DP  - 2014 Nov
TI  - Storage and secretion of naturally occurring von Willebrand factor A domain 
      variants.
PG  - 529-40
LID - 10.1111/bjh.13074 [doi]
AB  - Von Willebrand disease (VWD) is a bleeding disorder characterized by reduced 
      plasma von Willebrand factor (VWF) levels or functionally abnormal VWF. Low VWF 
      plasma levels in VWD patients are the result of mutations in the VWF gene that 
      lead to decreased synthesis, impaired secretion, increased clearance or a 
      combination thereof. However, expression studies of variants located in the A 
      domains of VWF are limited. We therefore characterized the biosynthesis of VWF 
      mutations, located in the VWF A1-A3 domains, that were found in families 
      diagnosed with VWD. Human Embryonic Kidney 293 (HEK293) cells were transiently 
      transfected with plasmids encoding full-length wild-type VWF or mutant VWF. Six 
      mutations in the A1-A3 domains were expressed. We found that all mutants, except 
      one, showed impaired formation of elongated pseudo-Weibel-Palade bodies (WPB). In 
      addition, two mutations also showed reduced numbers of pseudo-WPB, even in the 
      heterozygous state, and increased endoplasmic reticulum retention, which is in 
      accordance with the impaired regulated secretion seen in patients. Regulated 
      secretion upon stimulation of transfected cells reproduced the in vivo situation, 
      indicating that HEK293 cells expressing VWF variants found in patients with VWD 
      can be used to properly assess defects in regulated secretion.
CI  - (c) 2014 John Wiley & Sons Ltd.
FAU - Groeneveld, Dafna J
AU  - Groeneveld DJ
AD  - Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis 
      and Hemostasis, Leiden University Medical Centre, Leiden, The Netherlands.
FAU - Wang, Jiong-Wei
AU  - Wang JW
FAU - Mourik, Marjon J
AU  - Mourik MJ
FAU - Dirven, Richard J
AU  - Dirven RJ
FAU - Valentijn, Karine M
AU  - Valentijn KM
FAU - Voorberg, Jan
AU  - Voorberg J
FAU - Reitsma, Pieter H
AU  - Reitsma PH
FAU - Eikenboom, Jeroen
AU  - Eikenboom J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140808
PL  - England
TA  - Br J Haematol
JT  - British journal of haematology
JID - 0372544
RN  - 0 (von Willebrand Factor)
SB  - IM
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - *Mutation
MH  - Protein Structure, Tertiary
MH  - Weibel-Palade Bodies/genetics/*metabolism
MH  - von Willebrand Diseases/genetics/*metabolism/pathology
MH  - von Willebrand Factor/genetics/*metabolism
OTO - NOTNLM
OT  - Weibel-Palade body
OT  - secretion
OT  - storage
OT  - von Willebrand disease
OT  - von Willebrand factor
EDAT- 2014/08/12 06:00
MHDA- 2015/03/12 06:00
CRDT- 2014/08/09 06:00
PHST- 2014/05/22 00:00 [received]
PHST- 2014/07/04 00:00 [accepted]
PHST- 2014/08/09 06:00 [entrez]
PHST- 2014/08/12 06:00 [pubmed]
PHST- 2015/03/12 06:00 [medline]
AID - 10.1111/bjh.13074 [doi]
PST - ppublish
SO  - Br J Haematol. 2014 Nov;167(4):529-40. doi: 10.1111/bjh.13074. Epub 2014 Aug 8.