Mutations in the A3 domain of Von Willebrand factor inducing combined qualitative and quantitative defects in the protein

Legendre, Paulette; Navarrete, Ana-Maria; Rayes, Julie; Casari, Caterina; Boisseau, Pierre; Ternisien, Catherine; Caron, Claudine; Fressinaud, Édith; Goudemand, Jenny; Veyradier, Agnès; Denis, Cécile V.; Lenting, Peter J.; Olivier, Christophe

doi:10.1182/blood-2012-09-456038

Cited by 23 publications

(32 citation statements)

References 25 publications

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“…This result raised the possibility that the mutant protein was cleared more rapidly than wild-type VWF in vivo , a feature that cannot be detected in vitro . Mice expressing the second A3 domain mutant, p.P1824H-VWF also displayed low expression VWF levels, but the probable underlying cause, intracellular retention was this time detected both in the in vitro and the in vivo expression systems 41. For both mutants, the thrombotic response in arterioles of mice was strongly decreased, but the low expression levels did not allow concluding as whether this effect should be attributed to the quantitative defect or to the qualitative defect.…”

Section: Analysis Of Mice Reproducing Different Subtypes Of Human Vwdmentioning

confidence: 96%

“…As mentioned earlier, only murine VWF is hemostatically active in the mouse, preventing use of human VWF. However, since we had generated an active human-murine VWF chimera (hVWFmA1) in order to test the anti-thrombotic effect of monoclonal antibodies inhibiting specific VWF functions,24 we also used the same construct to introduce VWF mutations present in the A3 domain and detected in patients with VWD 41. Mutations in the VWF A3 domain have not been described as frequently as mutations in the platelet-binding domain (the A1 domain) but they are now being increasingly recognized 42–44.…”

Section: Analysis Of Mice Reproducing Different Subtypes Of Human Vwdmentioning

confidence: 99%

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Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned About VWF Functions

Casari¹,

Denis²

2013

Mediterr J Hematol Infect Dis

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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.

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Section: Analysis Of Mice Reproducing Different Subtypes Of Human Vwdmentioning

confidence: 96%

Section: Analysis Of Mice Reproducing Different Subtypes Of Human Vwdmentioning

confidence: 99%

Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned About VWF Functions

Casari¹,

Denis²

2013

Mediterr J Hematol Infect Dis

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“…The A3 domain is able to interact with various types of collagen, including collagens I & III, and the complementary binding sequences in collagen I and III have been deciphered in detail 82–85. The importance of the A3 domain in binding to collagen is supported by the finding that mutations in or around the collagen binding site may be associated with an increased bleeding tendency 86–89…”

Section: The Classical Functions Of Vwf: Collagen Bindingmentioning

confidence: 99%

On the Versatility of Von Willebrand Factor

Lenting¹

2013

Mediterr J Hematol Infect Dis

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Von Willebrand factor (VWF) is a large multimeric protein, the function of which has been demonstrated to be pivotal to the haemostatic system. Indeed, quantitative and/or qualitative abnormalities of VWF are associated with the bleeding disorder Von Willebrand disease (VWD). Moreover, increased plasma concentrations of VWF have been linked to an increased risk for thrombotic complications. In the previous decades, many studies have contributed to our understanding of how VWF is connected to the haemostatic system, particularly with regard to structure-function relationships. Interactive sites for important ligands of VWF (such as factor VIII, collagen, glycoprotein Ibα, integrin αIIbβ3 and protease ADAMTS13) have been identified, and mutagenesis studies have confirmed the physiological relevance of the interactions between VWF and these ligands. However, we have also become aware that VWF has a more versatile character than previously thought, given its potential role in various non-hemostatic processes, like intimal thickening, tumor cell apoptosis and inflammatory processes. In the presence review, a summary of our knowledge on VWF structure-function relationships is provided in the context of the “classical” haemostatic task of VWF and in perspective of pathological processes beyond haemostasis.

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“…The standard functional assays for VWD detection do not always evaluate the collagen-binding function of VWF (VWF:CB), and assays for diverse collagen types are even less common, which may have contributed to the scarcity of reported VWF:CB deficiencies [3]. Functional and molecular studies focused on this VWF dysfunction have increasingly reported VWF sequence variations that affect the ability of VWF to bind type I, type III and type VI collagen [3][4][5][6]. However, some of these mutations may not interfere with the screening assays, which show normal values, and can only be detected using type VI collagen.…”

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confidence: 99%

“…First, the well-characterized mutation that involved the same hydrophobic linear amino acids (p.Ala1716Pro) was associated with type 1 VWD, although this association was based solely on the VWF: Ag and VWF:RCo levels [10]. Second, one study described two mutations in the A3 domain that led to a combined qualitative and quantitative defect in VWF that exhibited decreased binding to collagen (types I and III) and the platelet glycoproteins Ib and IIb-IIIa [6].…”

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VWF collagen (types III and VI)‐binding defects in a cohort of type 2M VWD patients – a strategy for improvement of a challenging diagnosis

et al. 2017

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that osteochondral changes should be avoided, the true clinical relevance of early osteochondral changes is not established. Future studies need to focus on the clinical relevance of these small osteochondral changes and synovial hypertrophy using a longitudinal design and examining of HEAD-US scores in healthy adults of different age groups to provide reference values. In joints with more distinct findings on HJHS, additional HEAD-US examination in order to monitor osteochondral changes seems less useful. These distinct findings are generally due to osteochondral changes and can, if needed, be visualized by X-ray. Moreover, osteophytes and (very) limited range of motion limit the possibilities of ultrasound.In conclusion, in adults with haemophilia, HEAD-US may have additional value to HJHS by detecting the origin of slightly impaired function, or in revealing of early osteochondral changes in apparently healthy joints. The clinical relevance of these minimal changes still needs to be explored. In joints with more pronounced osteochondral changes, additional value of HEAD-US to monitor osteochondral changes seems limited. DisclosuresThis study and the ultrasound machine were supported by an unrestricted grant from Pfizer. References

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Mutations in the A3 domain of Von Willebrand factor inducing combined qualitative and quantitative defects in the protein

Abstract: Key PointsVWF A3 domain mutations inducing defective collagen binding and impaired protein production.

Cited by 23 publications

References 25 publications

Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned About VWF Functions

Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned About VWF Functions

On the Versatility of Von Willebrand Factor

VWF collagen (types III and VI)‐binding defects in a cohort of type 2M VWD patients – a strategy for improvement of a challenging diagnosis

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