Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice. Blood

Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Blood (Impact Factor: 10.45). 09/2009; 114(26):5368-74. DOI: 10.1182/blood-2009-07-233213
Source: PubMed


Type 1 von Willebrand disease (VWD) is the most common inherited human bleeding disorder. However, diagnosis is complicated by incomplete penetrance and variable expressivity, as well as wide variation in von Willebrand factor (VWF) levels among the normal population. Previous work has exploited the highly variable plasma VWF levels among inbred strains of mice to identify 2 major regulators, Mvwf1 and Mvwf2 (modifier of VWF). Mvwf1 is a glycosyltransferase and Mvwf2 is a natural variant in Vwf that alters biosynthesis. We report the identification of an additional alteration at the Vwf locus (Mvwf5), as well as 2 loci unlinked to Vwf (Mvwf6-7) using a backcross approach with the inbred mouse strains WSB/EiJ and C57BL/6J. Through positional cloning, we show that Mvwf5 is a cis-regulatory variant that alters Vwf mRNA expression. A similar mechanism could potentially explain a significant percentage of human VWD cases, especially those with no detectable mutation in the VWF coding sequence. Mvwf6 displays conservation of synteny with potential VWF modifier loci identified in human pedigrees, suggesting that its ortholog may modify VWF in human populations.

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    • "Large multicenter studies in Europe, Canada and United States have recently contributed to shed light on the complex mechanisms at the basis of type 1 VWD.26–28 These may involve defective RNA or protein synthesis, intracellular protein degradation, impaired secretion, rapid plasma clearance, all of which can result from either a mutation in the VWF gene or the presence of modifier genes interfering with VWF biology.3,29,30 What has become increasingly clear from these studies, is the absolute need for multiple approaches to identify these complex and sometimes multiple mechanisms. "
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    ABSTRACT: Up until recently, von Willebrand Factor (VWF) structure-function relationships have only been studied through in vitro approaches. A powerful technique known as hydrodynamic gene transfer, which allows transient expression of a transgene by mouse hepatocytes, has led to an important shift in VWF research. Indeed this approach has now enabled us to transiently express a number of VWF mutants in VWF-deficient mice in order to test the relative importance of specific residues in different aspects of VWF biology and functions in an in vivo setting. As a result, mice reproducing various types of von Willebrand disease have been generated, models that will be useful to test new therapies. This approach also allowed a more precise identification of the importance of VWF interaction with subendothelial collagens and with platelets receptors in hemostasis and thrombosis. The recent advances gathered from these studies as well as the pros and cons of the technique will be reviewed here.
    Full-text · Article · Jul 2013 · Mediterranean Journal of Hematology and Infectious Diseases
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    • "In contrast, the F1 mice from a cross of B6-Chr5 × B6-Chr17 restored the prolonged clot stability to the elevated consomic values (Hoover-Plow et al. 2006). Likewise, other studies (Shavit et al. 2009) have reported several loci that modify the von Willibrand factor that is required for platelet aggregation, and Hasstedt et al. (1998) suggested that there was a modifier gene for protein C that increases thromboembolism risk. "
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    ABSTRACT: Two overlapping quantitative trait loci (QTLs) for clot stability, Hmtb8 and Hmtb9, were identified on mouse chromosome 17 in an F2 intercross derived from C57BL/6J (B6) and B6-Chr17A/J (B6-Chr17) mouse strains. The intervals were in synteny with a QTL for thrombotic susceptibility on chromosome 18 in a human study, and there were 23 homologs between mouse and human. The objective of this study was to determine whether any of these genes in the syntenic region are likely candidates as modifiers for clot stability. Seven genes, Twsg1, Zfp161, Dlgap1, Ralbp1, Myom1, Rab31, and Emilin2, of the 23 genes with single nucleotide polymorphisms (SNPs) in the mRNA-UTR had differential expression in B6 and A/J mice. Dlgap1, Ralbp1, Myom1, and Emilin2 also had nonsynonymous SNPs. In addition, two other genes had nonsynonymous SNPs, Lama1 and Ndc80. Of these nine candidate genes, Emilin2 was selected for further analysis since other EMILIN (Elastin Microfibril Interface Located Protein) proteins have known functions in vascular structure and coagulation. Differences were found between B6 and A/J mice in vessel wall architecture and EMILIN2 protein in plasma, carotid vessel wall, and thrombi formed after ferric chloride injury. In B6-Chr17A/J mice both clot stability and Emilin2 mRNA expression were higher compared to those in B6 and A/J mice, suggesting the exposure of epistatic interactions. Although other homologous genes in the QTL region cannot be ruled out as causative genes, further investigation of Emilin2 as a candidate gene for thrombosis susceptibility is warranted. Electronic supplementary material The online version of this article (doi:10.1007/s00335-010-9274-6) contains supplementary material, which is available to authorized users.
    Preview · Article · Aug 2010 · Mammalian Genome
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    ABSTRACT: In this issue of Blood, Shavit and colleagues take advantage of major differences in von Willebrand factor gene (VWF) expression between inbred mouse strains to identify both a VWF locus alteration (Mvwf5) and 2 unlinked modifier gene loci (Mvwf6-7) that regulate plasma VWF levels.
    Preview · Article · Dec 2009 · Blood
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