Storage and secretion of naturally occurring von Willebrand factor A domain variants

被引:9
|
作者
Groeneveld, Dafna J. [1 ]
Wang, Jiong-Wei [1 ,2 ]
Mourik, Marjon J. [3 ]
Dirven, Richard J. [1 ]
Valentijn, Karine M. [3 ]
Voorberg, Jan [4 ]
Reitsma, Pieter H. [1 ]
Eikenboom, Jeroen [1 ]
机构
[1] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Dept Thrombosis & Hemostasis, NL-2300 RC Leiden, Netherlands
[2] NUS, NUHCS, Cardiovasc Res Inst CVRI, Dept Surg, Singapore, Singapore
[3] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands
[4] Sanquin AMC Landsteiner Lab, Dept Plasma Prot, Amsterdam, Netherlands
关键词
storage; secretion; von Willebrand disease; von Willebrand factor; Weibel-Palade body; WEIBEL-PALADE BODIES; OUTGROWTH ENDOTHELIAL-CELLS; REGULATED SECRETION; INCREASED SUSCEPTIBILITY; INTRACELLULAR STORAGE; CLINICAL MARKERS; FACTOR-VIII; A1; DOMAIN; DISEASE; TYPE-1;
D O I
10.1111/bjh.13074
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:529 / 540
页数:12
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