Insights into pathological mechanisms of missense mutations in C-terminal domains of von Willebrand factor causing qualitative or quantitative von Willebrand disease

Yadegari, Hamideh; Driesen, Julia; Pavlova, Anna; Biswas, Arijit; Ivaškevičius, Vytautas; Klamroth, Robert; Oldenburg, Johannes

doi:10.3324/haematol.2013.084111

Cited by 12 publications

(20 citation statements)

References 38 publications

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“…Gene conversion mutations identified in 5 (5%) patients in the present study were similar to other studies (2.9%‐18.5%) . In another study, the occurrence of the mutation p.Gln1311* was found to be associated with the development of inhibitors . However, in our series of patients, we did not observe the presence of inhibitors.…”

Section: Discussionsupporting

confidence: 90%

“…8,41,46 In another study, the occurrence of the mutation p.Gln1311* was found to be associated with the development of inhibitors. 35 However, in our series of patients, we did not observe the presence of inhibitors. This may also be because inhibitors were only checked if there was lack of clinical response and not as a matter of scheduled screening.…”

Section: Discussioncontrasting

confidence: 65%

“…Structural analysis was performed for only 4 mutations, while other missense changes were analysed using in silico analysis tools. Previously reported mutations (n = 6) were considered disease causative 30,[32][33][34][35][36] (Table 1).…”

Section: Mutationsinpatientswithvwdmentioning

confidence: 99%

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Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Elayaperumal

Fouzia

Biswas³

et al. 2018

Haemophilia

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 65%

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Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Elayaperumal

Fouzia

Biswas³

et al. 2018

Haemophilia

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“…Laboratory investigation of VWF antigen (VWF:Ag), VWF binding to platelet glycoprotein Ib, factor VIII coagulant activity, and VWF multimers (1.2% [w/v] and 1.6% [w/v] agarose gels) was performed as previously described. 4,22 The bleeding score was calculated on the basis of a bleeding questionnaire for type 1 VWD. 23 This study was approved by the local ethics committee, and informed consent was obtained from all patients (vote 091/09).…”

Section: Patients: Phenotypic Analysismentioning

confidence: 99%

“…2 Deficient VWF results in von Willebrand disease (VWD), which is classified as quantitative (type 1 and type 3) or qualitative (type 2). 3,4 Type 1 VWD, characterized by partial reduction in VWF levels, is the most common form of the disorder. 5 Inheritance of type 1 VWD is considered to be autosomal dominant; however, in ;15% of index cases, more than a single candidate VWF variant is detected.…”

Section: Introductionmentioning

confidence: 99%

Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5′ splice site

Yadegari¹,

Biswas²,

Akhter³

et al. 2016

Blood

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Key Points• This study demonstrates allosteric RNA structure alteration resulting from an exonic variation, thereby interfering with splicing.• This study details a novel mechanism by which silent mutation distant to the 59 splice site could still result in intron retention.Disease-associated silent mutations are considered to affect the accurate premessenger RNA (mRNA) splicing either by influencing regulatory elements, leading to exon skipping, or by creating a new cryptic splice site. This study describes a new molecular pathological mechanism by which a silent mutation inhibits splicing and leads to intron retention. We identified a heterozygous silent mutation, c.7464C>T, in exon 44 of the von Willebrand factor (VWF) gene in a family with type 1 von Willebrand disease. In vivo and ex vivo transcript analysis revealed an aberrantly spliced transcript, with intron 44 retained in the mRNA, implying disruption of the first catalytic step of splicing at the 59 splice site (59ss). The abnormal transcript with the retained intronic region coded a truncated protein that lacked the carboxy-terminal end of the VWF protein. Confocal immunofluorescence characterizations of blood outgrowth endothelial cells derived from the patient confirmed the presence of the truncated protein by demonstrating accumulation of VWF in the endoplasmic reticulum. In silico pre-mRNA secondary and tertiary structure analysis revealed that this substitution, despite its distal position from the 59ss (85 bp downstream), induces cis alterations in pre-mRNA structure that result in the formation of a stable hairpin at the 59ss. This hairpin sequesters the 59ss residues involved in U1 small nuclear RNA interactions, thereby inhibiting excision of the pre-mRNA intronic region. This study is the first to show the allosteric-like/far-reaching effect of an exonic variation on pre-mRNA splicing that is mediated by structural changes in the pre-mRNA. (Blood. 2016;128(17):2144-2152

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von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention

Yadegari¹,

Biswas²,

Ahmed

et al. 2021

Human Mutation

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von Willebrand disease (VWD), the most prevalent congenital bleeding disorder, arises from a deficiency in von Willebrand factor (VWF), which has crucial roles in hemostasis. The present study investigated functional consequences and underlying pathomolecular mechanisms of several VWF propeptide (VWFpp) missense variants detected in our cohort of VWD patients for the first time. Transient expression experiments in HEK293T cells demonstrated that four out of the six investigated missense variants (p.Gly55Glu, p.Val86Glu, p.Trp191Arg, and p.Cys608Trp) severely impaired secretion. Their cotransfections with the wild‐type partly corrected VWF secretion, displaying loss of large/intermediate multimers. Immunostaining of the transfected HEK293 cells illustrated the endoplasmic reticulum (ER) retention of the VWF variants. Docking of the COP I and COP II cargo recruitment proteins, ADP‐ribosylation factor 1 and Sec24, onto the N‐terminal VWF model (D1D2DʹD3) revealed that these variants occur at VWFpp putative interfaces, which can hinder VWF loading at the ER exit quality control. Furthermore, quantitative and automated morphometric exploration of the three‐dimensional immunofluorescence images showed changes in the number/size of the VWF storage organelles, Weibel‐Palade body (WPB)‐like vesicles. The result of this study highlighted the significance of the VWFpp variants on anterograde ER‐Golgi trafficking of VWF as well as the biogenesis of WPB‐like vesicles.

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Insights into pathological mechanisms of missense mutations in C-terminal domains of von Willebrand factor causing qualitative or quantitative von Willebrand disease

Cited by 12 publications

References 38 publications

Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5′ splice site

von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention

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