Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phenotypic and Genotypic Characterization of von Willebrand Factor Gene (Exon 18 and 20) in Saudi Healthy Individuals

ABSTRACT:

Introduction:

Von Willebrand disease (VWD) is an autosomal congenital bleeding syndrome that was described as being the most widespread genetic condition among men. In Saudi Arabia, the genotyping of the VWF gene is necessary to establish a diagnosis procedure for VWD.

Aim:

The current research, however, attempted to evaluate the phenotypic-genotypic association of the Von Willebrand factor (exon 18 and 20) gene in healthy subjects to establish effective molecular diagnostic strategies.

Methods:

This was a cross-sectional retrospective included 100 healthy people who have been chosen from King Fahad University Hospital. Whole blood samples were collected from all individuals, as well as the laboratory analysis was done using automatic analyzers for; platelet count, ABO blood group and coagulation parameters. DNA Sanger sequencing has been used to sequestrate the full exons 18 and 20.

Results:

In exon 18 of healthy people, three unusual sequence variations (1 missense and 2 synonymous; rs775479826, rs1286572448 and rs369828268) compared to other recorded VWF variations (3 missense and 1 synonymous; c.2365A > G, c.2385T > C, c.2344C > T and c.2340C > G). But in exon 20 only 1 synonymous novel (rs113240752) 1 registered VWF variations in missense (c.2555G > A) were identified.

Conclusion:

The present variants found on those participates could be a realistic approach to detect mutation in the VWF gene to illustrating the relationship of phenotypic and genetic abnormalities variables may lead to determining the functional effect in mutations specific to the Saudi people that can be used to develop a diagnostic tool for VWD in KSA.

SUBMITTER: Alzahrani F

PROVIDER: S-EPMC7780826 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Phenotypic and Genotypic Signatures of <i>VWF</i> Exon 18 in Eastern Saudi Patients Previously Diagnosed with Type 1 von Willebrand Disease.

Project description:Introductionvon Willebrand disease (VWD) is the most prevalent bleeding disease, which is associated with either low levels of von Willebrand factor (VWF) or abnormality in its structure. Three types of the disease have been described; type 1 (VWD1) and 3 (VWD3) are caused by deficiency of VWF and type 2 (VWD2) is caused by production of defective VWF. The aim of the current study was to characterize gene variants of VWF gene; exon 18 in particular, in a cohort of Saudi families as well as healthy control subjects.MethodsA total of 19 families comprising 60 subjects of type 1 VWD were enrolled in the study. Participants were divided into 22 index cases, 21 affected family members and 17 unaffected family members ranging in age from 6 to 70 years. Blood samples were collected from all participants to measure activated partial thromboplastin time test (APTT), von Willebrand antigen level (VWF:Ag), Factor VIII activity (FVIII:C) and ristocetin cofactor activity (VWF:RCo), platelet count, determining the ABO blood group and for genetic analysis by Sanger sequencing.ResultsThe results indicated that VWD1 patients have lower levels of VWF and factor VIII than the non-affected family members and the control subjects. In addition, five gene variants were reported in VWF exon 18; of these, c.2365A>G and c.2385T>C were more common in the control group and might be protective from VWD.DiscussionIn conclusion, VWF levels are influenced by blood group, and there was no association between variants in exon 18 of VWF gene reported in all groups and the disease status; however, blood group analysis and genome-wide genotyping could help to highlight high-risk groups and improve clinical management of VWD.

| S-EPMC9170233 | biostudies-literature

Classification of exon 18 linked variants of VWF gene in von Willebrand disease.

Project description:Defects in von Willebrand factor, a crucial protein in haemostasis, lead to the most common inherited coagulopathy in man, von Willebrand disease. To date, over 350 mutations and 170 single nucleotide polymorphisms of VWF gene have been reported. In the present study, the distribution of two linked VWF gene variants, rs1063856 and rs1063857 have been assessed. The proportional frequency of rs1063856 (2365A/G) and rs1063857 (2385T/C) in healthy individuals were 0.70/0.30. Frequency of polymorphisms was in agreement with predicted geographical distribution. von Willebrand disease was more common in subjects with 2365A and 2385T alleles (odds ratio=1.35), although the difference was not statistically significant (p-values>0.05). The perfect correlation between these two single nucleotide polymorphisms supports their joint contribution in von Willebrand factor biology.

| S-EPMC3316446 | biostudies-literature

Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

Project description:Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.

| S-EPMC4497966 | biostudies-literature

von Willebrand disease.

Project description:von Willebrand disease 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-dependent platelet adhesion because of decreased high-molecular-weight von Willebrand factor multimers, (2) type 2B-caused by pathologically increased von Willebrand factor-platelet interactions, (3) type 2M-caused by decreased von Willebrand factor-platelet interactions not based on the loss of high-molecular-weight multimers, and (4) type 2N-characterized by reduced binding of von Willebrand factor to factor VIII. The diagnosis of von Willebrand disease requires specialized assays of von Willebrand factor and/or molecular genetic testing of von Willebrand factor. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally inactivated plasma-derived clotting factor concentrates containing both von Willebrand factor and factor VIII. Depending on the von Willebrand disease 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.

| S-EPMC3832952 | biostudies-literature

Phenotypic and genetic characterizations of the Milan cohort of von Willebrand disease type 2.

Project description:von Willebrand disease (VWD) type 2 is caused by qualitative abnormalities of von Willebrand factor (VWF). This study aimed to determine the genotypic and phenotypic characterizations of a large VWD type 2 cohort from Milan. We included 321 patients (54% female) within 148 unrelated families from 1995 to 2021. Patients were fully characterized using laboratory phenotypic tests, and the genotypic diagnosis was confirmed by target genetic analysis using Sanger sequencing. Patients were diagnosed with type 2A (n = 98; 48 families), 2B (n = 85; 38 families), 2M (n = 112; 50 families), or 2N (n = 26; 12 families). Eighty-two unique VWF variants, including 8 novel variants, were found. The potential pathogenic effect of novel variants was assessed by in silico analysis. Most patients were heterozygous for a single variant (n = 259; 81%), whereas 37 cases (11%) had 2 variants (4 homozygous, 9 in trans, and 24 in cis). Twenty-five patients (8%) had ≥3 variants, mainly as a result of gene conversions. Among the 82 distinct variants identified, 5 different types, including missense (n = 64), gene conversion (n = 10), synonymous (n = 1), deletion (n = 4), and splice (n = 3), were observed. The results from this large cohort showed that VWD type 2 is invariably due to variants that do not prevent the synthesis of the protein, and a vast majority of patients (88%) had missense variants. Given the complexity of type 2 diagnosis and the necessity of performing several phenotypic tests, genetic analysis for patients suspected of having type 2 is beneficial to establish the correct diagnosis.

| S-EPMC9278302 | biostudies-literature

A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient.

Project description:A translationally silent single nucleotide mutation in exon 44 (E44) of the von Willebrand factor (VWF) gene is associated with inefficient removal of intron 44 in a von Willebrand disease (VWD) patient. This intron retention (IR) event was previously attributed to reordered E44 secondary structure that sequesters the normal splice donor site. We propose an alternative mechanism: the mutation introduces a cryptic splice donor site that interferes with the function of the annotated site to favor IR. We evaluated both models using minigene splicing reporters engineered to vary in secondary structure and/or cryptic splice site content. Analysis of splicing efficiency in transfected K562 cells suggested that the mutation-generated cryptic splice site in E44 was sufficient to induce substantial IR. Mutations predicted to vary secondary structure at the annotated site also had modest effects on IR and shifted the balance of residual splicing between the cryptic site and annotated site, supporting competition among the sites. Further studies demonstrated that introduction of cryptic splice donor motifs at other positions in E44 did not promote IR, indicating that interference with the annotated site is context dependent. We conclude that mutant deep exon splice sites can interfere with proper splicing by inducing IR.

| S-EPMC8706089 | biostudies-literature

Intracellular storage and regulated secretion of von Willebrand factor in quantitative von Willebrand disease.

Project description:Several missense mutations in the von Willebrand Factor (VWF) gene of von Willebrand disease (VWD) patients have been shown to cause impaired constitutive secretion and intracellular retention of VWF. However, the effects of those mutations on the intracellular storage in Weibel-Palade bodies (WPBs) of endothelial cells and regulated secretion of VWF remain unknown. We demonstrate, by expression of quantitative VWF mutants in HEK293 cells, that four missense mutations in the D3 and CK-domain of VWF diminished the storage in pseudo-WPBs, and led to retention of VWF within the endoplasmic reticulum (ER). Immunofluorescence and electron microscopy data showed that the pseudo-WPBs formed by missense mutant C1060Y are indistinguishable from those formed by normal VWF. C1149R, C2739Y, and C2754W formed relatively few pseudo-WPBs, which were often short and sometimes round rather than cigar-shaped. The regulated secretion of VWF was impaired slightly for C1060Y but severely for C1149R, C2739Y, and C2754W. Upon co-transfection with wild-type VWF, both intracellular storage and regulated secretion of all mutants were (partly) corrected. In conclusion, defects in the intracellular storage and regulated secretion of VWF following ER retention may be a common mechanism underlying VWD with a quantitative deficiency of VWF.

| S-EPMC3129199 | biostudies-literature

Improving diagnosis of von Willebrand disease: Reference ranges for von Willebrand factor multimer distribution.

Project description:BackgroundPhenotypic von Willebrand disease (VWD) classification requires multiple tests including analysis of multimeric distributions von Willebrand factor (VWF) and evaluation of its structure. VWF multimer analysis is labor intensive, nonstandardized, and limited to specialized laboratories. A commercial semiautomatic assay, HYDRAGEL VW multimer assay (H5/11VWM, Sebia), has become available.ObjectivesEstablishment of reference ranges for H5/11VWM to improve VWD classification.MethodsImplementation validation, establishment and validation of normal and pathological reference intervals (NRIs/PRIs), comparison with in-house method using 40 healthy volunteers and 231 VWD patients.ResultsQualitative and quantitative validation of NRI obtained sensitivity of 88% and 79%, respectively, for type 2. Comparison of the two methods showed an overall concordance of 86% with major conflicting results in all atypical 2B (n = 7) and 50% 2M-GPIb (n = 41) showing quantitative and qualitative multimeric loss, that was not detected with in-house method. We were able to use established PRIs, with 73% validity in type 2 cases, to distinguish individual type 2A subtypes (IIA, IIC, IID, IIE) from 2M and 2B.ConclusionH5/11VWM could be used for all clinical purposes because its reliability and its rapid and accurate diagnostic ability and reduced observer bias. Although H5/11VWM cannot evaluate triplet structures, we were able to define 2A subtypes by stripping back to the percentage of intermediate/high-molecular-weight multimers. H5/11HWM could be an efficient and widely available alternative for the "gold standard" technique.

| S-EPMC7443431 | biostudies-literature

Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients.

Project description:von Willebrand factor (VWF) level and function are influenced by genetic variation in VWF and several other genes in von Willebrand disease type 1 (VWD1) patients. This study comprehensively screened for VWF variants and investigated the presence of ABO genotypes and common and rare VWF variants in Swedish VWD1 patients. The VWF gene was resequenced using Ion Torrent and Sanger sequencing in 126 index cases historically diagnosed with VWD. Exon 7 of the ABO gene was resequenced using Sanger sequencing. Multiplex ligation-dependent probe amplification analysis was used to investigate for copy number variants. Genotyping of 98 single nucleotide variants allowed allele frequency comparisons with public databases. Seven VWD2 mutations and 36 candidate VWD1 mutations (5 deletions, 4 nonsense, 21 missense, 1 splice, and 5 synonymous mutations) were identified. Nine mutations were found in more than one family and nine VWD1 index cases carried more than one candidate mutation. The T-allele of rs1063857 (c.2385T > C, p.Y795 = ) and blood group O were both frequent findings and contributed to disease in the Swedish VWD1 population. VWD2 mutations were found in 20 and candidate VWD1 mutations in 51 index cases out of 106 (48%). VWF mutations, a VWF haplotype, and blood group O all contributed to explain disease in Swedish VWD1 patients.

| S-EPMC6524857 | biostudies-literature

Effect of von Willebrand factor on gene expression in HUVECs

Project description:Von Willebrand factor is a paracrine/autocrine regulator of human mesenchymal stem cell adhesion to distressed/apoptotic endothelial cells. This data set examines effect of vWF on gene expression in HUVECs.

2010-11-10 | GSE19816 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data