Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Ahmed, Shariq; Yadegari, Hamideh; Naz, Arshi; Biswas, Arijit; Budde, Ulrich; Saqlain, Nazish; Amanat, Samina; Tariq, Shehla; Raziq, Fazle; Masood, Shahtaj; Pavlova, Anna; Shamsi, Tahir; Oldenburg, Johannes

doi:10.1111/hae.13841

Cited by 7 publications

(12 citation statements)

References 33 publications

(150 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VWD3 has been investigated in several studies, and .300 different gene variants have been reported. [7][8][9][10] The majority of these studies involved small groups of patients, and the authors have either focused on clinical symptoms and biochemical phenotype or on the patients' genotype. 6,7 The 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study) is an investigator-initiated, multicenter, European/Iranian observational study that aims to comprehensively evaluate the clinical symptoms of VWD3 patients, 11 their phenotypic laboratory findings, and the VWF variants, as well as the safety and efficacy of replacement therapy for the treatment and prevention of bleeding manifestations (registered at www.clinicaltrials.gov as #NCT02460458).…”

Section: Introductionmentioning

confidence: 99%

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

et al. 2021

Self Cite

View full text Add to dashboard Cite

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Causative VWF variants were identified in all 44 type 3 subjects with 93% of the mutant alleles accounted for, which is consistent with other type 3 VWD studies that have reported between 80%-95% of cases with pathogenic variants. 4,[7][8][9][10] Of the variants identified, 9% were large heterozygous deletions of exon 1-3, exon 4-5, exon 18 and exon 35-38. The exon 4-5 in-frame deletion has been previously reported as the most common deletion in the VWF gene occurring in both type 1 and type 3 VWD.…”

Section: Discussionmentioning

confidence: 99%

“…A thorough genetic evaluation included VWF Sanger sequencing, comparative genomic hybridization (aCGH) and in silico prediction programs. While several large type 3 studies have been previously reported, 4,[7][8][9][10] the results provided here from the Zimmerman Program represents a cohort of VWD families in the U.S. with extensive phenotypic and genotypic data and provides additional insight into the bleeding tendencies, inheritance and phenotypic heterogeneity in families with type 3 VWD.…”

Section: Introduction/backg Roundmentioning

confidence: 99%

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

Christopherson

Haberichter

Flood

et al. 2022

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). Objectives As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. Patients/Methods 62 index cases with a pre‐existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs. Results 75% of subjects (46) had central testing confirming type 3, while 25% were re‐classified as type 1‐Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co‐dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. Conclusion This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co‐dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

show abstract

“…The VWD diagnosis and classification of the IPs were made based on bleeding symptoms and standard coagulation tests, consistent with ISTH‐SSC VWF guidelines (Sadler et al, 2006). The VWF analysis was before performed in Bonn Haemophilia Center, and the result of the genetic analysis, as well as coagulation tests, has been previously reported (Ahmed et al, 2019; Yadegari et al, 2012). DNA and protein sequence numbering has been done based on the reference sequence: RefSeq NM_000552.4 and NP_000543.2, respectively, and sequence variant descriptions were verified by VariantValidator online tool (https://variantvalidator.org/; accessed on September 20, 2020).…”

Section: Methodsmentioning

confidence: 99%

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

Yadegari¹,

Biswas²,

Ahmed

et al. 2021

Human Mutation

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Cited by 7 publications

References 33 publications

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

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

Contact Info

Product

Resources

About