ArticleHuman mutation2010
The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria.
Article in Human mutation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Data-driven insights to inform splice-altering variant assessment.American journal of human genetics · 2025Article
- A single-cell strategy for the identification of intronic variants related to mis-splicing in pancreatic cancer.NAR genomics and bioinformatics · 2024Article
- Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing.Orphanet journal of rare diseases · 2023Article
- Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene.Nucleic acid therapeutics · 2022Article
- Subcutaneous vitamin B12 administration using a portable infusion pump in cobalamin-related remethylation disorders: a gentle and easy to use alternative to intramuscular injections.Orphanet journal of rare diseases · 2021Article
- In silico identification of pseudo-exon activation events in personal genome and transcriptome data.RNA biology · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation.Journal of clinical immunology · 2020Article
- The Asthma-associated PER1-like domain-containing protein 1 (PERLD1) Haplotype Influences Soluble Glycosylphosphatidylinositol Anchor Protein (sGPI-AP) Levels in Serum and Immune Cell Proliferation.Scientific reports · 2020Article
- Activation of cryptic splice sites in three patients with chronic granulomatous disease.Molecular genetics & genomic medicine · 2019Article
- Article
- Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome.European journal of human genetics : EJHG · 2018Article
- Deep intronic mutations and human disease.Human genetics · 2017Review
- Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation.Journal of molecular medicine (Berlin, Germany) · 2017Article
- Global identification of hnRNP A1 binding sites for SSO-based splicing modulation.BMC biology · 2016Article
- Article
- Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.Clinical journal of the American Society of Nephrology : CJASN · 2015Article
- Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells.Nucleic acids research · 2015Article
- Next-generation sequencing ofMolecular and clinical oncology · 2014Article
- Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis.F1000Research · 2014Review
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6 authors.
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Abstract
Deep intronic mutations are often ignored as possible causes of human diseases. A deep intronic mutation in the MTRR gene, c.903+469T>C, is the most frequent mutation causing the cblE type of homocystinuria. It is well known to be associated with pre-mRNA mis-splicing, resulting in pseudoexon inclusion; however, the pathological mechanism remains unknown. We used minigenes to demonstrate that this mutation is the direct cause of MTRR pseudoexon inclusion, and that the pseudoexon is normally not recognized due to a suboptimal 5' splice site. Within the pseudoexon we identified an exonic splicing enhancer (ESE), which is activated by the mutation. Cotransfection and siRNA experiments showed that pseudoexon inclusion depends on the cellular amounts of SF2/ASF and in vitro RNA-binding assays showed dramatically increased SF2/ASF binding to the mutant MTRR ESE. The mutant MTRR ESE sequence is identical to an ESE of the alternatively spliced MST1R proto-oncogene, which suggests that this ESE could be frequently involved in splicing regulation. Our study conclusively demonstrates that an intronic single nucleotide change is sufficient to cause pseudoexon activation via creation of a functional ESE, which binds a specific splicing factor. We suggest that this mechanism may cause genetic disease much more frequently than previously reported.
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