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Open AccessArticle

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

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Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France
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Cell Imaging Core Facility of the Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Imagine and Paris Descartes University, 75015 Paris, France
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Service D’exploration de la Vision et Neuro-Ophtalmologie, Pôle D’imagerie et Explorations Fonctionnelles, CHRU de Lille, 59037 Lille, France
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Department of Ophthalmology, IHU Necker-Enfants Malades, 75015 Paris, France
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Unit of Retinal Degeneration and Regeneration, Department of Ophthalmology, University of Lausanne, Hôpital Ophtalmique Jules Gonin, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland
*
Authors to whom correspondence should be addressed.
Genes 2019, 10(5), 368; https://doi.org/10.3390/genes10050368
Received: 29 March 2019 / Revised: 9 May 2019 / Accepted: 9 May 2019 / Published: 14 May 2019
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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. View Full-Text
Keywords: Leber congenital amaurosis and allied retinal ciliopathies; CEP290; Flanders founder c.4723A > T nonsense mutation; Cilia elongation; spontaneous nonsense correction; AON-mediated exon skipping Leber congenital amaurosis and allied retinal ciliopathies; CEP290; Flanders founder c.4723A >; T nonsense mutation; Cilia elongation; spontaneous nonsense correction; AON-mediated exon skipping
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Barny, I.; Perrault, I.; Michel, C.; Goudin, N.; Defoort-Dhellemmes, S.; Ghazi, I.; Kaplan, J.; Rozet, J.-M.; Gerard, X. AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction? Genes 2019, 10, 368.

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