ArticlePloS one2013
Unexpected CEP290 mRNA splicing in a humanized knock-in mouse model for Leber congenital amaurosis.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 62 citations in OpenAlex.
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- Non-viral gene therapy for Leber's congenital amaurosis: progress and possibilities.Nanomedicine (London, England) · 2025Review
- Early Developmental Characteristics and Features of a Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis.International journal of molecular sciences · 2024Article
- A humanized knock-inbioRxiv : the preprint server for biology · 2024Article
- Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models.International journal of molecular sciences · 2024Review
- Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases.Stem cell research & therapy · 2023Review
- Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics.Nucleic acid therapeutics · 2023Article
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- Eupatilin improves cilia defects in human CEP290 ciliopathy models.bioRxiv : the preprint server for biology · 2023Article
- Consensus Guidelines for the Design andNucleic acid therapeutics · 2023Article
- Patient stem cell-derived in vitro disease models for developing novel therapies of retinal ciliopathies.Current topics in developmental biology · 2023Review
- Generation of Humanized Zebrafish Models for the In Vivo Assessment of Antisense Oligonucleotide-Based Splice Modulation Therapies.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Considerations for Generating Humanized Mouse Models to Test Efficacy of Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities.Frontiers in molecular neuroscience · 2022Review
- Delivery of Antisense Oligonucleotides to the Mouse Retina.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Primary cilia biogenesis and associated retinal ciliopathies.Seminars in cell & developmental biology · 2021Review
- Toward the Treatment of Inherited Diseases of the Retina Using CRISPR-Based Gene Editing.Frontiers in medicine · 2021Review
- Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art.Frontiers in medicine · 2021Review
- Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies.Animals : an open access journal from MDPI · 2020Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leber congenital amaurosis (LCA) is the most severe form of retinal dystrophy with an onset in the first year of life. The most frequent genetic cause of LCA, accounting for up to 15% of all LCA cases in Europe and North-America, is a mutation (c.2991+1655AG) in intron 26 of CEP290. This mutation generates a cryptic splice donor site resulting in the insertion of an aberrant exon (exon X) containing a premature stop codon to CEP290 mRNA. In order to study the pathophysiology of the intronic CEP290 mutation, we generated two humanized knock-in mouse models each carrying ~6.3 kb of the human CEP290 gene, either with or without the intronic mutation. Transcriptional characterization of these mouse models revealed an unexpected splice pattern of CEP290 mRNA, especially in the retina. In both models, a new cryptic exon (coined exon Y) was identified in ~5 to 12% of all Cep290 transcripts. This exon Y was expressed in all murine tissues analyzed but not detected in human retina or fibroblasts of LCA patients. In addition, exon x that is characteristic of LCA in humans, was expressed at only very low levels in the retina of the LCA mouse model. Western blot and immunohistochemical analyses did not reveal any differences between the two transgenic models and wild-type mice. Together, our results show clear differences in the recognition of splice sites between mice and humans, and emphasize that care is warranted when generating animal models for human genetic diseases caused by splice mutations.
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