A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3

Sutherland, M. S.; Cumming, A. M.; Bowman, Mackenzie; Bolton‐Maggs, Paula; Bowen, Derrick John; Collins, Peter William; Hay, C. R. M.; Will, Andrew; Keeney, S.

doi:10.1182/blood-2008-08-173278

Cited by 40 publications

(51 citation statements)

References 40 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34–36 Missense mutations predominate but may affect VWF through different mechanisms. A common heterozygous in-frame large deletion of exons 4–5 has recently been reported in a cohort of UK type 1 VWD patients 43 and this along with similar large deletions may also contribute to the mutation spectrum in this disease type. As molecular genetic testing has only been undertaken in type 1 VWD relatively recently, pathogenic mechanisms have not yet been ascertained in many cases.…”

Section: Molecular Genetic Testingmentioning

confidence: 79%

von Willebrand disease

James

Goodeve

2011

Genetics in Medicine

View full text Add to dashboard Cite

von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery and/or childbirth and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: 1) type 2A - characterized by defective von Willebrand factor (VWF) -dependent platelet adhesion because of decreased high molecular weight (HMW) VWF multimers, 2) type 2B - caused by pathologically increased VWF-platelet interactions, 3) type 2M - caused by decreased VWF-platelet interactions not based on the loss of HMW multimers and 4) type 2N - characterized by abnormal binding of VWF to FVIII. The diagnosis of VWD requires specialized assays of von Willebrand factor (VWF) and/or molecular genetic testing of VWF. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally-inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII. Depending on the VWD type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia.

show abstract

Section: Molecular Genetic Testingmentioning

confidence: 79%

von Willebrand disease

James

Goodeve

2011

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…In this patient, the mutation is a deletion of VWF exons 4 and 5, corresponding to the D1 region of the VWF propeptide, 21,37 which is involved in multimerization. BOECs from this patient show defective processing of pre-pro VWF, which appears to be retained in the ER and fails to be properly packaged into WPBs.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells

Starke

Paschalaki

Dyer

et al. 2013

Blood

View full text Add to dashboard Cite

disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease. (Blood. 2013;121(14):2773-2784

show abstract

“…The most commondeletion in the vWF mutation database is c.2435delCin exon 18. Deletion of exons 4 and 5 is reported to bea recurrent deletion in the UK, and is associated with a common haplotype and founder effect [45]. Although it isa rare complication, development of alloantibodies againstvWF is observed in association with large deletions andwhole gene deletion (Table 2) [39,46,47].…”

Section: Introductionmentioning

confidence: 99%

The Molecular Genetics of von Willebrand Disease

Berber¹

2012

Turk J Hematol

View full text Add to dashboard Cite

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.Conflict of interest:None declared.

show abstract

A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3

Cited by 40 publications

References 40 publications

von Willebrand disease

von Willebrand disease

Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells

The Molecular Genetics of von Willebrand Disease

Contact Info

Product

Resources

About