ArticleBlood2016
Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5' splice site.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 39 citations in OpenAlex.
- Interplay between circulating von Willebrand factor and neutrophils: implications for inflammation, neutrophil function, and von Willebrand factor clearance.Haematologica · 2025Article
- A Novel Synonymous Variant of PAX2 in Monochorionic Diamniotic Twins With Bilateral Renal Agenesis: A Case Report and Literature Review.Molecular genetics & genomic medicine · 2025Review
- The Establishment of Artificial RNA Cascade Circuits for Gene Regulation Based on Doxycycline-Induced Pre-mRNA Alternative Splicing.International journal of molecular sciences · 2025Article
- How does precursor RNA structure influence RNA processing and gene expression?Bioscience reports · 2023Review
- The variant rs77559646 associated with aggressive prostate cancer disrupts ANO7 mRNA splicing and protein expression.Human molecular genetics · 2022Article
- Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.Research and practice in thrombosis and haemostasis · 2022Article
- A Homozygous Deep Intronic Variant Causes Von Willebrand Factor Deficiency and Lack of Endothelial-Specific Secretory Organelles, Weibel-Palade Bodies.International journal of molecular sciences · 2022Article
- Multifaceted pathomolecular mechanism of a VWF large deletion involved in the pathogenesis of severe VWD.Blood advances · 2022Article
- A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient.International journal of molecular sciences · 2021Article
- Systematics for types and effects of RNA variations.RNA biology · 2021Article
- A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient.Molecular genetics & genomic medicine · 2020Article
- Machine Learning Approaches for the Prioritization of Genomic Variants Impacting Pre-mRNA Splicing.Cells · 2019Review
- Unraveling the effect of silent, intronic and missense mutations onHaematologica · 2019Article
- Efficient scarless genome editing in human pluripotent stem cells.Nature methods · 2018Article
- The genetic background of antibiotic resistance among clinical uropathogenic Escherichia coli strains.Molecular biology reports · 2018Article
- Detection of genomic structural variations in Guizhou indigenous pigs and the comparison with other breeds.PloS one · 2018Article
- Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients.Haematologica · 2017Article
- A study of splicing mutations in disorders of sex development.Scientific reports · 2017Article
- Intron retention as a component of regulated gene expression programs.Human genetics · 2017Review
- New Genetic Variation in BCR gene of Major B3a2 Breakpoint BCR-ABL Fusion Gene in Patients with Chronic Myelogenous Leukemia in Yogyakarta, IndonesiaAsian Pacific journal of cancer prevention : APJCP · 2017Article
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7 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Disease-associated silent mutations are considered to affect the accurate pre-messenger 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 5' splice site (5'ss). 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 5'ss (85 bp downstream), induces cis alterations in pre-mRNA structure that result in the formation of a stable hairpin at the 5'ss. This hairpin sequesters the 5'ss 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.
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