ArticleInternational journal of molecular sciences2015
Species-dependent splice recognition of a cryptic exon resulting from a recurrent intronic CEP290 mutation that causes congenital blindness.
Article in International journal of molecular sciences, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 27 citations in OpenAlex.
- Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models.International journal of molecular sciences · 2024Review
- Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics.Nucleic acid therapeutics · 2023Article
- The Predicted Splicing Variant c.11+5G>A inCells · 2022Article
- Exon Skipping Through Chimeric AntisenseNucleic acid therapeutics · 2022Article
- Considerations for Generating Humanized Mouse Models to Test Efficacy of Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Delivery of oligonucleotide-based therapeutics: challenges and opportunities.EMBO molecular medicine · 2021Review
- Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies.Animals : an open access journal from MDPI · 2020Article
- The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements.Journal of clinical medicine · 2019Article
- The use of genetically humanized animal models for personalized medicine approaches.Disease models & mechanisms · 2019Review
- Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.Molecular therapy. Nucleic acids · 2018Article
- Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance.Human mutation · 2017Article
- Delivery is key: lessons learnt from developing splice-switching antisense therapies.EMBO molecular medicine · 2017Review
- Unraveling the mysteries of pre-mRNA splicing in the retina via stem cell technology.Stem cell investigation · 2016Article
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A mutation in intron 26 of CEP290 (c.2991+1655A>G) is the most common genetic cause of Leber congenital amaurosis (LCA), a severe type of inherited retinal degeneration. This mutation creates a cryptic splice donor site, resulting in the insertion of an aberrant exon (exon X) into ~50% of all CEP290 transcripts. A humanized mouse model with this mutation did not recapitulate the aberrant CEP290 splicing observed in LCA patients, suggesting differential recognition of cryptic splice sites between species. To further assess this phenomenon, we generated two CEP290 minigene constructs, with and without the intronic mutation, and transfected these in cell lines of various species. RT-PCR analysis revealed that exon X is well recognized by the splicing machinery in human and non-human primate cell lines. Intriguingly, this recognition decreases in cell lines derived from species such as dog and rodents, and it is completely absent in Drosophila. In addition, other cryptic splicing events corresponding to sequences in intron 26 of CEP290 were observed to varying degrees in the different cell lines. Together, these results highlight the complexity of splice site recognition among different species, and show that care is warranted when generating animal models to mimic splice site mutations in vivo.
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