Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit.

Verweij, Cornelis L.; Diergaarde, Paul J.; Hart, Mia van der; Pannekoek, Hans

doi:10.1002/j.1460-2075.1986.tb04435.x

Cited by 259 publications

(158 citation statements)

References 43 publications

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“…Type 2 VWD is further divided into four subtypes: type 2N is characterized by abnormal binding of VWF to FVIII, type 2A by defective VWF-dependent platelet adhesion because of decreased high molecular weight (HMW) VWF multimers, type 2B by pathologically increased VWF-platelet interactions leading to the depletion of HMW VWF multimers, and type 2M by decreased VWF-platelet interactions not caused by the loss of HMW multimers [4]. The VWF gene was cloned and characterized by four groups simultaneously in 1985 [5][6][7][8], allowing for an improved understanding of the molecular basis of VWD.…”

Section: Introductionmentioning

confidence: 99%

Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

Notley

Hegadorn

et al. 2007

Journal of Thrombosis and Haemostasis

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Summary. Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18-52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type 1 VWD Study as type 1 VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL -1 on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. Results: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chisquared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A1 domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. Conclusions: The genotypephenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.

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Section: Introductionmentioning

confidence: 99%

Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

Notley

Hegadorn

et al. 2007

Journal of Thrombosis and Haemostasis

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“…It is synthesized as pre-pro-VWF, a single chain polypeptide with the domain structure D1-D2-DЈ-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK (7). The pro-VWF molecule is subject to extensive posttranslational modifications, including carboxyl-terminal dimerization (8).…”

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confidence: 99%

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Lenting

Westein

Terraube

et al. 2004

Journal of Biological Chemistry

136

189

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To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t1 ⁄2 ␣ ‫؍‬ 13 min) and a slow secondary phase (t1 ⁄2 ␤ ‫؍‬ 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of fulllength VWF to truncated variants. Deletion of both the amino-terminal D -D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D -D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT ‫؍‬ 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT ‫؍‬ 4.5 h, p < 0.02). These results point to a role of the D -D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT ‫؍‬ 0.3 h; p ‫؍‬ 0.004). Therefore, this mutation seems to abrogate the protective effect of the D -D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.von Willebrand factor (VWF) 1 is a multimeric plasma protein that participates in the hemostatic process. The absence of functional VWF is associated with an abnormal bleeding tendency known as von Willebrand Disease (VWD) (1, 2). VWF contributes to hemostasis in a dual manner. First, it promotes the adhesion of platelets at sites of vascular injury by acting as a molecular bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex glycoprotein (Gp) Ib␣/IX/V (3). In addition, VWF serves as a carrier protein for coagulation factor VIII (FVIII) in the circulation. This chaperone function results in stabilization of the FVIII heterodimeric structure (4) and protection of FVIII from premature clearance by the low density lipoprotein receptor-related protein (5, 6).VWF is produced and stored in endothelial cells and megakaryocytes. It is synthesized as pre-pro-VWF, a single chain polypeptide with the domain structure

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“…The attachment to human pp-vWF was comparable to that to bovine pp-vWF and not affected at all by the RGD peptide. Although the amino acid sequence deduced from the cDNA of human vWF precursor contains an RGD sequence at residues 676-678 [22], bovine pp-vWF has a sequence X-G-S instead in this position [21]. It seems likely that the RGD site (residues 676-678) in human ppvWF cannot function as a cell adhesion site for B16 cells.…”

Section: Resultsmentioning

confidence: 99%

β1‐integrin‐mediated adhesion of melanoma cells to the propolypeptide of von Willebrand factor

Takagi

Sudo

Saito

et al. 1994

European Journal of Biochemistry

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Cell-adhesion activity of the bovine propolypeptide of von Willebrand factor (pp-vWF) was assessed by means of an in vitro assay with several cell lines of both normal and tumor-cell origin. pp-vWF promoted adhesion and spreading of B16 mouse melanoma cells and G-361 human melanoma cells. However, it could not induce adhesion of any other cell lines tested including endothelial cells, normal fibroblasts, and tumor cells of sarcoma, carcinoma, neuroblastoma and leukemia origin. A monospecific polyclonal antibody against pp-vWF, but not against fibronectin, laminin, and von Willebrand factor (vWF), completely blocked the pp-vWF-mediated adhesion, indicating that the cell adhesion was due to the pp-vWF molecule and not due to possible contamination of these three well-known adhesive proteins. The cell-adhesion activity was also observed with human ppvWF and, furthermore, the adhesion to both bovine and human pp-vWF was not affected by a peptide containing the Arg-Gly-Asp sequence while the peptide abolished the cell adhesion to vWF. The adhesion was completely dependent on Mg2+ and inhibited by Ca"'. Inhibition by an anti-(pl integrin) mAb (4B4) indicates that the receptor for this protein belongs to the pl-integrin family. A monoclonal antibody (TC4) among several antibodies directed against bovine pp-vWF inhibited the B16 adhesion to immobilized pp-vWF. The epitope for this monoclonal antibody lies in a central 8-kDa portion of pp-vWF, suggesting that this region is important for the cell-adhesion activity. This idea was supported by the finding that purified 8-kDa fragment promoted adhesion of B16 cells in a concentration-dependent manner. As pp-vWF shows unique cell-type specificity in its adhesion activity, which is completely different from that of fibronectin, laminin, vWF and collagen, it may be a novel type of adhesive glycoprotein that utilizes a Dl-integrin receptor.The adhesion of cells to extracellular matrix (ECM) proteins is a key step involved in modulating the morphology, proliferation, differentiation, and migration of cells. This process is mediated by interactions between specific cell surface receptors and specific matrix proteins. Different cells adhere to different adhesive proteins due to the differential expression of surface receptors. It is well known that many cells adhere to fibronectin, laminin and collagen through more than one class of receptors including various integrins [ l , 21. Although these three proteins are abundant in ECM and thought to be primarily important in tissue organization under physiological conditions, there are a number of other proteins that have cell-adhesion activity in vitro and are thought to play a crucial role in more specialized stages of cellular events. [7]. A large amount of evidence is accumulating that these adhesive glycoproteins play dynamic roles in embryo-

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Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit.

Cited by 259 publications

References 43 publications

Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

β1‐integrin‐mediated adhesion of melanoma cells to the propolypeptide of von Willebrand factor

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