The Von Willebrand Factor Propeptide (VWFpp) Traffics an Unrelated Protein to Storage

Haberichter, Sandra L.; Jozwiak, Mary A.; Rosenberg, Jonathan B.; Christopherson, Pamela A.; Montgomery, Robert R.

doi:10.1161/01.atv.0000017063.36768.87

Cited by 37 publications

(39 citation statements)

References 30 publications

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“…12,13 Our previous studies have demonstrated that VWF storage is initiated by VWFpp: VWFpp contains the "signal" for trafficking to granules and secondarily cotraffics mature VWF by virtue of a noncovalent association. 14,15 However, VWF granular storage and multimerization have also been shown to be independent processes: multimerization is not necessary for granular storage. 12,[15][16][17] Here we report the characterization of a Turkish consanguineous family diagnosed with type 2A VWD.…”

Section: Introductionmentioning

confidence: 99%

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Haberichter

Budde²,

Obser

et al. 2010

Blood

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We characterized a consanguineous Turkish family suffering from von Willebrand disease (VWD) with significant mucocutaneous and joint bleeding. The relative reduction of large plasma von Willebrand factor (VWF) multimers and the absent VWF triplet structure was consistent with type 2A (phenotype IIC) VWD. Surprisingly, platelet VWF was completely deficient of multimers beyond the VWF protomer, suggesting defective ␣-granular storage of larger multimers. Patients were nearly unresponsive to desmopressin acetate, consistent with a lack of regulated VWF release from endothelial cell Weibel-Palade bodies, suggesting defective storage also in endothelial cells. We identified an N528S homozygous mutation in the VWF propeptide D2 domain, predicting the introduction of an additional N-glycosylation site at amino acid 526 in close vicinity to a "CGLC" disulphide isomerase consensus sequence. Expression studies in mammalian cells demonstrated that N528S-VWF was neither normally multimerized nor trafficked to storage granules. However, propeptide containing the N528S mutation trafficked normally to storage granules. Our data indicate that the patients' phenotype is the result of defective multimerization, storage, and secretion. In addition, we have identified a potentially novel pathogenic mechanism of VWD, namely a transportation and storage defect of mature VWF due to defective interaction with its transporter, the mutant propeptide. (Blood. 2010;115(22): 4580-4587)

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Section: Introductionmentioning

confidence: 99%

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Haberichter

Budde²,

Obser

et al. 2010

Blood

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“…17,18 Previous studies in our laboratory have demonstrated that VWF is sorted to regulated storage vesicles in a VWFpp-dependent manner. 19,20 Our studies were carried out using the mouse pituitary model cell line AtT-20 and bovine aortic endothelial cells (BAECs) that have endogenousregulated storage granules containing adrenocorticotrophic hormone (ACTH) or bovine VWF, respectively. We have demonstrated that the propeptide independently sorts to endogenous storage granules in these cells and co-traffics mature VWF multimers through a noncovalent association.…”

Section: Introductionmentioning

confidence: 99%

“…We have demonstrated that the propeptide independently sorts to endogenous storage granules in these cells and co-traffics mature VWF multimers through a noncovalent association. 19,21 However, because of the presence of endogenous-regulated secretory vesicles, these studies could not address the biogenesis of the regulated storage vesicle.…”

Section: Introductionmentioning

confidence: 99%

Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells

Haberichter

Merricks

Fahs

et al. 2005

Blood

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“…Interestingly, the mean t1/2 value of VWFpp after DDAVP administration in the patients was 100 min (range: 85-115 min) which is shorter than that previously reported in normal individuals (2-3 h). [16][17][18] Some temporary correction of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios was observed ( Figures 3E and F). Noticeable quantitative differences were seen among the three families of patients.…”

Section: Resultsmentioning

confidence: 99%

Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications

Pérez‐Rodríguez

García-Rivero²,

Lourés³

et al. 2009

Haematologica

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BackgroundMutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD). Design and MethodsEight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not described in earlier studies. ResultsThe patients showed notably low levels of VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding (VWF:CB), and a reduced ristocetininduced platelet aggregation (RIPA). VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were lower than 0.7. At basal conditions, all the VWF multimers were decreased in plasma, with a clearly lower relative proportion of the high molecular weight VWF multimers (HMWM). In high-resolution agarose gels, a large decrease in the relative proportions of the satellite bands was seen. The patients had a brief good response to desmopressin (DDAVP) administration, but the released VWF half-life was shorter than normal, indicating an accelerated clearance of their VWF. Platelet VWF was abnormal. ConclusionsWe conclude from the results obtained in these patients for plasma phenotypic data that this mutation should be classified as a VWD type 2A (IIE). DDAVP therapy may be somewhat helpful for this mutation, at least for mild to moderate bleeding. These data provide evidence that for VWD classification factors other than basal VWF, such as DDAVP response and platelet VWF, should be considered.

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The Von Willebrand Factor Propeptide (VWFpp) Traffics an Unrelated Protein to Storage

Cited by 37 publications

References 30 publications

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells

Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications

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