AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?
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... Mehr ...
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Dokumenttyp: | Artikel |
Erscheinungsdatum: | 2019 |
Schlagwörter: | Antigens / Neoplasm/genetics / 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 > / Leber congenital amaurosis and allied retinal ciliopathies / T nonsense mutation / spontaneous nonsense correction |
Sprache: | Englisch |
Permalink: | https://search.fid-benelux.de/Record/base-27086904 |
Datenquelle: | BASE; Originalkatalog |
Powered By: | BASE |
Link(s) : | https://serval.unil.ch/notice/serval:BIB_0B5866B8F244 |
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.