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Hum Mol Genet. 2018 May 16. doi: 10.1093/hmg/ddy179. [Epub ahead of print]

Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease.

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Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
Cell Imaging Core Facility of the Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Imagine and Paris Descartes University, 75015 Paris, France.
Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, 75015 Paris, France and Department of Genetics, CHU Henri Mondor, 94010 Créteil, France.
Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
Centre de Référence des Affections Sensorielles Génétiques, Institut des Neurosciences de Montpellier, CHU-Saint Eloi Montpellier, 34091 Montpellier, France.
Centre de Référence pour les Affections Génétiques Ophtalmologiques CARGO, CHRU Strasbourg, INSERM 1112, Université de Strasbourg, 67000 Strasbourg, France.


CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base-pair deletion in exon 17, introducing a premature termination codon (PTC) in exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in exon 8 (c.508A>T, p.Lys170*) and exon 32 (c.4090G>T, p.Glu1364*), respectively. Some CEP290 lacking exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing (NAS) alone (exon 8), or with BES (exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.


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