Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients

Abstract

von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, , and . Here, we comprehensively screen for variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of . The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. showed a high level of linkage disequilibrium and a low overall nucleotide diversity of = 3.2 × 10 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare mutations contribute to type 1 VWD in the Swedish population.

Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

“…The coding sequences of exons 1 to 3 and exons 5 to 7 of CLEC4M had been sequenced previously using Sanger sequencing, 13 as had all exons of STXBP5 . 14 There was complete concordance between the sets of variants detected by Sanger and Ion Torrent sequencing for all individuals.…”

“…We would like to argue against this since the average read depths were >300 for seven of the eight genes, the coverage was high with only very few regions without coverage, and there was a complete concordance between the sets of variants detected by Sanger and Ion Torrent sequencing in CLEC4M and STXBP5 for all individuals. 13 14 Thus, we believe that the lack of accumulation of rare variants and the almost total absence of rare variants predicted to affect protein function in our VWD population is true. None of the genes, except the VWF gene itself, harbor large numbers of rare variants affecting the amount of VWF, ultimately giving rise to VWD.…”

“…Previous analysis of STXBP5 revealed two benign rare variants and a common missense variant (rs1039084) with a slightly increased allele frequency compared to controls. 14 STX2 had two rare missense variants, which were possibly damaging, and one common missense variant, which was benign. TC2N had four benign missense variants with the same allele frequencies as the control populations.…”

Proteomics to Identify New Blood Biomarkers for Diagnosing Patients With Acute Stroke

“…In particular, STXBP5 regulates the secretion of von Willebrand factor (VWF), a glycoprotein with an important role in hemostasis, especially by promoting platelet adhesion. 40 STXBP5 mutations were associated with reduced plasma VWF levels and VWF activity, 40 , 41 while STXBP5 genetic variations may increase the risk of thromboembolic disease. 42 STXBP5 also seems to promote the release of tPA from endothelial cells.…”

<p>Long noncoding RNA STXBP5-AS1 inhibits cell proliferation, migration, and invasion through inhibiting the PI3K/AKT signaling pathway in gastric cancer cells</p>

“…The significant finding is that STXBP5 was linked to GC 12. STXBP5 was associated with type 1 von Willebrand disease13 and found to participate in tumor processes 11. STXBP5 has also been identified as influenced by PI3K/AKT 11…”