AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_0B5866B8F244
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?
Périodique
Genes
Auteur⸱e⸱s
Barny I., Perrault I., Michel C., Goudin N., Defoort-Dhellemmes S., Ghazi I., Kaplan J., Rozet J.M., Gerard X.
ISSN
2073-4425 (Print)
ISSN-L
2073-4425
Statut éditorial
Publié
Date de publication
14/05/2019
Peer-reviewed
Oui
Volume
10
Numéro
5
Langue
anglais
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
Mutations in CEP290 encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo-lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated-altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation.
Mots-clé
Antigens, Neoplasm/genetics, Antigens, Neoplasm/metabolism, Cell Cycle Proteins/genetics, Cell Cycle Proteins/metabolism, Codon, Nonsense, Cytoskeletal Proteins/genetics, Cytoskeletal Proteins/metabolism, Exons/genetics, Eye Abnormalities/genetics, Eye Diseases, Hereditary/genetics, Humans, Male, Neoplasm Proteins/genetics, Oligonucleotides, Antisense/genetics, RNA Splicing, Retina/metabolism, Retinal Dystrophies/genetics, Retinal Dystrophies/physiopathology, AON-mediated exon skipping, CEP290, Cilia elongation, Flanders founder c.4723A &gt, Leber congenital amaurosis and allied retinal ciliopathies, T nonsense mutation, spontaneous nonsense correction
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/05/2019 14:12
Dernière modification de la notice
30/04/2021 6:08
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