ArticlePloS one2015
Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- The Role of Urea Cycle Functional Studies in Preclinical Research.Journal of inherited metabolic disease · 2026Review
- Cell modeling and rescue of a novel noncoding genetic cause of glycogen storage disease IX.Genetics in medicine open · 2026Article
- Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models.Journal of inherited metabolic disease · 2025Article
- Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe OTC deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Preclinical assessment of splicing modulation therapy for ABCA4 variant c.768G>T in Stargardt disease.Communications medicine · 2025Article
- Exploring RNA therapeutics for urea cycle disorders.Journal of inherited metabolic disease · 2024Review
- PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.Human molecular genetics · 2024Article
- Modelling urea cycle disorders using iPSCs.NPJ Regenerative medicine · 2022Review
- Pathogenic variants of ornithine transcarbamylase deficiency: Nation-wide study in Japan and literature review.Frontiers in genetics · 2022Article
- OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfMolecular medicine (Cambridge, Mass.) · 2021Article
- Correction of a urea cycle defect after ex vivo gene editing of human hepatocytes.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Delivery of oligonucleotide-based therapeutics: challenges and opportunities.EMBO molecular medicine · 2021Review
- Gene Editing Correction of a Urea Cycle Defect in Organoid Stem Cell Derived Hepatocyte-like Cells.International journal of molecular sciences · 2021Article
- An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-DefectiveInternational journal of molecular sciences · 2020Article
- Ex Vivo Enteroids Recapitulate In Vivo Citrulline Production in Mice.The Journal of nutrition · 2018Article
- Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).PloS one · 2016Article
- Correction: Functional Characterization of the spf/ash Splicing Variation in OTC Deficiency of Mice and Man.PloS one · 2015Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The spf/ash mouse model of ornithine transcarbamylase (OTC) deficiency, a severe urea cycle disorder, is caused by a mutation (c.386G>A; p.R129H) in the last nucleotide of exon 4 of the Otc gene, affecting the 5' splice site and resulting in partial use of a cryptic splice site 48 bp into the adjacent intron. The equivalent nucleotide change and predicted amino acid change is found in OTC deficient patients. Here we have used liver tissue and minigene assays to dissect the transcriptional profile resulting from the "spf/ash" mutation in mice and man. For the mutant mouse, we confirmed liver transcripts corresponding to partial intron 4 retention by the use of the c.386+48 cryptic site and to normally spliced transcripts, with exon 4 always containing the c.386G>A (p.R129H) variant. In contrast, the OTC patient exhibited exon 4 skipping or c.386G>A (p.R129H)-variant exon 4 retention by using the natural or a cryptic splice site at nucleotide position c.386+4. The corresponding OTC tissue enzyme activities were between 3-6% of normal control in mouse and human liver. The use of the cryptic splice sites was reproduced in minigenes carrying murine or human mutant sequences. Some normally spliced transcripts could be detected in minigenes in both cases. Antisense oligonucleotides designed to block the murine cryptic +48 site were used in minigenes in an attempt to redirect splicing to the natural site. The results highlight the relevance of in depth investigations of the molecular mechanisms of splicing mutations and potential therapeutic approaches. Notably, they emphasize the fact that findings in animal models may not be applicable for human patients due to the different genomic context of the mutations.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.