von Willebrand disease in the RIIIS/J mouse is caused by a defect outside of the von Willebrand factor gene

Nichols, William C.; Cooney, Kathleen A.; Mohlke, Karen L.; Ballew, Jeffrey D.; Yang, Angela; Bruck, Mary E.; Reddington, Madonna; Novak, Edward K.; Swank, Richard T.; Ginsburg, David

doi:10.1182/blood.v86.6.2461.bloodjournal8662461

Cited by 34 publications

(29 citation statements)

References 33 publications

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“…While there is a significant body of evidence to indicate that types 2A and 2B VWD are almost always autosomal dominant traits because of mutations within the VWF gene [37–41] and that type 2N [39,42] and type 3 [43,44] VWD variants are recessive VWF gene traits, there is little information concerning the location and types of mutation that result in the quantitative type 1 phenotype. Reports of both dominant [45,46] and recessive [47,48] inheritance patterns have been published, and in at least one mouse model of type 1 disease, the causative genetic locus is not the VWF gene [7,9]. Nevertheless, there is a growing appreciation that this condition represents a complex genetic trait [49,50] and there has also been recent renewed debate about the definition of the diagnosis [51,52].…”

Section: Discussionmentioning

confidence: 99%

“…The gene that encodes von Willebrand factor (VWF) is located on chromosome 12p13.3, and was cloned and characterized by a number of groups simultaneously in 1984 [2–5]. Although the 1994 Revised ISTH Classification of VWD [6] states that ‘All VWD is caused by mutations at the VWF locus’ there has been a growing appreciation that additional genetic loci may play important roles in regulating VWF biosynthesis and ultimately determining the plasma level of the protein [7–9]. Twin, and other family‐based studies, in normal and ‘hypercoagulable’ pedigrees, have shown that the heritability of VWF plasma levels (the proportion of variation that can be attributed to additive genetic factors) ranges between 32% and 75% [10–14].…”

Section: Introductionmentioning

confidence: 99%

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Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian Type 1 VWD Study

James

Paterson

Notley

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. Background: von Willebrand disease (VWD) is the most common bleeding disorder known in humans, with type 1 VWD representing the majority of cases. Unlike the other variant forms of VWD, type 1 disease represents a complex genetic trait, influenced by both genetic and environmental factors. Aim: To evaluate the contribution of the von Willebrand factor (VWF) and ABO blood group loci to the type 1 VWD phenotype, and to assess the potential for locus heterogeneity in this condition, we have performed genetic linkage and association studies on a large, unselected type 1 VWD population. Method: We initially collected samples from 194 Canadian type 1 VWD families for analysis. After the exclusion of families found to have either type 2 or type 3 VWD, and pedigrees with samples from single generations, linkage and association analysis was performed on 155 type 1 VWD families. Results and conclusion: The linkage study has shown a low heterogeneity LOD score of 2.13 with the proportion of families linked to the VWF gene estimated to be 0.41. Linkage was not detected to the ABO locus in this type 1 VWD population. In the family-based association test, significant association was found between the type 1 VWD phenotype, the quantitative traits, VWF:Ag, VWF:RCo, and FVIII:C and the ABO ÔOÕ and ÔAÕ alleles and the VWF codon 1584 variant. There was also weak association with the )1185 promoter polymorphism and VWF:Ag, VWF:RCo, and FVIII:C plasma levels. These studies provide further evidence to support the role for genetic loci other than VWF and ABO in the pathogenesis of type 1 VWD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian Type 1 VWD Study

James

Paterson

Notley

et al. 2006

Journal of Thrombosis and Haemostasis

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“…This wrong posttranslational modification leads to a very rapid clearance of vWF from the circulation and the phenotypic expression similar to type I vWD. [36][37][38] In this article, we will summarize the data generated from infusion studies with mature fully processed recombinant vWF in dogs with severe vWD and address in vivo processing of pro-vWF as demonstrated after administration of pro-vWF into animals with severe vWD. In addition, we will discuss a newly discovered mechanism of vWF in preserving FVIII in the circulation as first demonstrated in vWF-deficient knockout mice.…”

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confidence: 99%

Recombinant von Willebrand Factor-Insight into Structure and Function through Infusion Studies in Animals with Severe von Willebrand Disease

Schwarz

Schlokat²,

Mitterer³

et al. 2002

Semin Thromb Hemost

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We used a canine and a murine model of von Willebrand disease (vWD) to study the in vivo effects of recombinant von Willebrand factor (vWF). Two preparations were used: (1) a fully processed mature vWF; this was achieved by coexpression of furin. (2) A preparation containing unprocessed pro-vWF, the propeptide still covalently linked to mature vWF. Both preparations induced an increase in canine and murine factor VIII:C (FVIII), which was sustained even when vWF antigen had been removed from the circulation. vWF multimers were analyzed in the plasma samples after infusion using ultra high-resolution 3% agarose gels to allow the separation of homoforms and heteroforms of the vWF polymers. Administration of pro-vWF to dogs with severe vWD resulted in the removal of the propeptide and maturation of vWF in the circulation, indicating that the propeptide cleavage from unprocessed vWF can occur extracellularly. This suggests that the vWF propeptide, besides being derived from the Weibel-Palade bodies of endothelial cells after stimulation, can also be cleaved by pro-vWF in plasma. Using a murine model of vWD, the involvement of the low-density lipoprotein receptor-related protein (LRP) in the clearance of FVIII was established. The low levels of FVIII observed in the absence of vWF are due to an enhanced clearance of FVIII by binding to LRP and removal from the circulation through endocytosis. Administration of the receptor-associated protein (RAP) as a recombinant fusion protein to vWF knockout mice significantly improved the in vivo recovery of recombinant FVIII and the survival time of otherwise rapidly cleared FVIII.

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“…The initial mouse model of mild VWD was the RIIIS/J mouse, in which the VWF is reduced secondary to accelerated clearance [30,31]. The cause of the reduced VWF is secondary to a glycosylation defect in which N-acetylgalactosaminyl transferase, B4GAL-NT2, is expressed ectopically in endothelial cells resulting in accelerated clearance in VWF.…”

Section: Discussionmentioning

confidence: 99%

von Willebrand’s disease diagnosis and laboratory issues

et al. 2010

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Summary In this paper, the recent developments in the diagnosis and laboratory issues of von Willebrand’s disease (VWD) are presented. Dr. Castaman reviews the functional tests available for the diagnosis of VWD and their pathophysiological significance, focusing on which tests are best used in the diagnosis and classification of VWD. Dr Montgomery reviews an emerging issue that is accelerated clearance of von Willebrand factor (VWF) occurring in some variants of VWD. This phenotype can be suspected by the presence of an increased ratio between the VWF propeptide and the VWF antigen. These patients have typically a robust, but short-lived increase of FVIII and VWF after desmopressin. Dr Meschengieser reviews the determinants of bleeding after surgery in patients with VWD, emphasizing the role of bleeding history in predicting this risk.

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von Willebrand disease in the RIIIS/J mouse is caused by a defect outside of the von Willebrand factor gene

Cited by 34 publications

References 33 publications

Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian Type 1 VWD Study

Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian Type 1 VWD Study

Recombinant von Willebrand Factor-Insight into Structure and Function through Infusion Studies in Animals with Severe von Willebrand Disease

von Willebrand’s disease diagnosis and laboratory issues

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