{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:18:59Z","timestamp":1790705939940,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T00:00:00Z","timestamp":1557792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNADEV\/AVIESAN","award":["R16074KS"],"award-info":[{"award-number":["R16074KS"]}]},{"name":"UNADEV\/AVIESAN","award":["R16073KS"],"award-info":[{"award-number":["R16073KS"]}]},{"name":"JED Belgique","award":["No Grant Number"],"award-info":[{"award-number":["No Grant Number"]}]},{"DOI":"10.13039\/501100013875","name":"Retina France","doi-asserted-by":"publisher","award":["No Grant Number"],"award-info":[{"award-number":["No Grant Number"]}],"id":[{"id":"10.13039\/501100013875","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2013lethal 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 &gt; 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\u2013altered 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 &gt; T mutation.<\/jats:p>","DOI":"10.3390\/genes10050368","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T10:42:33Z","timestamp":1557830553000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A &gt; T Mutation. Fact or Fiction?"],"prefix":"10.3390","volume":"10","author":[{"given":"Iris","family":"Barny","sequence":"first","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8560-1379","authenticated-orcid":false,"given":"Isabelle","family":"Perrault","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Michel","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Goudin","sequence":"additional","affiliation":[{"name":"Cell Imaging Core Facility of the Structure F\u00e9d\u00e9rative de Recherche Necker, INSERM US24\/CNRS UMS3633, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Defoort-Dhellemmes","sequence":"additional","affiliation":[{"name":"Service D\u2019exploration de la Vision et Neuro-Ophtalmologie, P\u00f4le D\u2019imagerie et Explorations Fonctionnelles, CHRU de Lille, 59037 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad","family":"Ghazi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, IHU Necker-Enfants Malades, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josseline","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7951-7886","authenticated-orcid":false,"given":"Jean-Michel","family":"Rozet","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Gerard","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France"},{"name":"Unit of Retinal Degeneration and Regeneration, Department of Ophthalmology, University of Lausanne, H\u00f4pital Ophtalmique Jules Gonin, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1080\/13816810802232768","article-title":"Leber congenital amaurosis: From darkness to spotlight","volume":"29","author":"Kaplan","year":"2008","journal-title":"Ophthalmic Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/humu.20010","article-title":"Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype\u2013phenotype correlations as a strategy for molecular diagnosis","volume":"23","author":"Hanein","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1083\/jcb.201006105","article-title":"CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content","volume":"190","author":"Craige","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.preteyeres.2008.05.003","article-title":"Leber congenital amaurosis: genes, proteins and disease mechanisms","volume":"27","author":"Roepman","year":"2008","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/humu.9485","article-title":"Spectrum of NPHP6\/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype","volume":"28","author":"Perrault","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/humu.20565","article-title":"Centrosomal-ciliary gene CEP290\/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: Implications for therapy of Leber congenital amaurosis","volume":"28","author":"Cideciyan","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_7","first-page":"244","article-title":"Lorenz, B. The Phenotypic spectrum of ophthalmic changes in CEP290 mutations","volume":"236","author":"Preising","year":"2019","journal-title":"Klin. Monbl. Augenheilkd"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1038\/mtna.2012.21","article-title":"AON-mediated exon skipping restores ciliation in fibroblasts harboring the common leber congenital amaurosis CEP290 mutation","volume":"1","author":"Gerard","year":"2012","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1038\/mtna.2012.3","article-title":"Antisense oligonucleotide (AON)-based therapy for leber congenital amaurosis caused by a frequent mutation in CEP290","volume":"1","author":"Collin","year":"2012","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_10","first-page":"769","article-title":"Identification and correction of mechanisms underlying inherited blindness in human iPSC-derived optic cups","volume":"18","author":"Parfitt","year":"2016","journal-title":"Cell. Stem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.omtn.2018.07.010","article-title":"Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+1655A>G LCA10 models","volume":"12","author":"Dulla","year":"2018","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_12","first-page":"2552","article-title":"In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery","volume":"25","author":"Garanto","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41591-018-0295-0","article-title":"Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect","volume":"25","author":"Cideciyan","year":"2019","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1056\/NEJMoa0802268","article-title":"Effect of gene therapy on visual function in Leber\u2019s congenital amaurosis","volume":"358","author":"Bainbridge","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1089\/hum.2008.107","article-title":"Treatment of leber congenital amaurosis due to rpe65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial","volume":"19","author":"Hauswirth","year":"2008","journal-title":"Hum. Gene Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1056\/NEJMoa0802315","article-title":"Safety and Efficacy of gene transfer for leber\u2019s congenital amaurosis","volume":"358","author":"Maguire","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6118","DOI":"10.1167\/iovs.13-11673","article-title":"Subretinal gene therapy of mice with bardet-biedl syndrome type 1","volume":"54","author":"Seo","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ejhg.2012.137","article-title":"Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome","volume":"21","author":"Neidhart","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1136\/jmg.2010.077883","article-title":"Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations","volume":"47","author":"Papon","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"291ra97","DOI":"10.1126\/scitranslmed.aaa5370","article-title":"Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis","volume":"7","author":"Drivas","year":"2015","journal-title":"Sci. Trans. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1093\/hmg\/ddy179","article-title":"Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease","volume":"15","author":"Barny","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3646","DOI":"10.1167\/iovs.09-5074","article-title":"A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype","volume":"51","author":"Littink","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Roosing, S., Cremers, F.P.M., Riemslag, F.C.C., Zonneveld-Vrieling, M.N., Talsma, H.E., Klessens-Godfroy, F.J.M., den Hollander, A.I., and van den Born, L.I. (2017). A rare form of retinal dystrophy caused by hypomorphic nonsense mutations in CEP290. Genes, 8.","DOI":"10.3390\/genes8080208"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1089\/hum.2013.234","article-title":"Development of therapeutic splice-switching oligonucleotides","volume":"25","author":"Disterer","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.devcel.2008.07.004","article-title":"CP110 Suppresses primary cilia formation through its interaction with cep290, a protein deficient in human ciliary disease","volume":"15","author":"Tsang","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1093\/hmg\/ddn277","article-title":"CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium","volume":"17","author":"Kim","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1091\/mbc.e12-02-0134","article-title":"The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium","volume":"23","author":"Stowe","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12489","DOI":"10.1073\/pnas.1809432115","article-title":"Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model","volume":"115","author":"Ramsbottom","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4525","DOI":"10.1172\/JCI69448","article-title":"Disruption of CEP290 microtubule\/membrane-binding domains causes retinal degeneration","volume":"123","author":"Drivas","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1093\/hmg\/ddv123","article-title":"CEP290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies","volume":"24","author":"Rachel","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1093\/hmg\/ddl107","article-title":"In-frame deletion in a novel centrosomal\/ciliary protein CEP290\/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse","volume":"15","author":"Chang","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.celrep.2017.06.045","article-title":"In Vitro modeling using ciliopathy-patient-derived cells reveals distinct cilia dysfunctions caused by CEP290 mutations","volume":"20","author":"Shimada","year":"2017","journal-title":"Cell Rep."},{"key":"ref_33","unstructured":"Barny, I., Perrault, I., Rio, M., Dollfus, H., Defoort-Dhellemmes, S., Kaplan, J., Rozet, J.-M., and Gerard, X. Description of two siblings with apparently severe CEP290 mutations and unusually mild retinal disease unrelated to basal exon skipping or nonsense-associated altered splicing. Adv. Exp. Med. Biol., (under review)."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S1383-5742(98)00010-6","article-title":"The association of nonsense codons with exon skipping","volume":"411","author":"Valentine","year":"1998","journal-title":"Mutat. Res.\/Rev. Mutat. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrg775","article-title":"Listening to silence and understanding nonsense: exonic mutations that affect splicing","volume":"3","author":"Cartegni","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1172\/JCI119757","article-title":"Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy","volume":"100","author":"Shiga","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1002\/humu.21337","article-title":"CEP290, a gene with many faces: Mutation overview and presentation of CEP290base","volume":"31","author":"Coppieters","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_38","first-page":"e88","article-title":"Differences in renal tubule primary cilia length in a mouse model of bardet-biedl syndrome","volume":"106","author":"Mokrzan","year":"2007","journal-title":"NEE"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1681\/ASN.2006020136","article-title":"Development of Polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease","volume":"17","author":"Smith","year":"2006","journal-title":"JASN"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1681\/ASN.2006090985","article-title":"Nek8 regulates the expression and localization of polycystin-1 and polycystin-2","volume":"19","author":"Sohara","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1093\/hmg\/ddp272","article-title":"Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3","volume":"18","author":"Tammachote","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/ncb2988","article-title":"The kinesin-4 protein KIF7 regulates mammalian hedgehog signaling by organizing the cilia tip compartment","volume":"16","author":"He","year":"2014","journal-title":"Nat. Cell. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1186\/s13059-015-0858-z","article-title":"KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome","volume":"16","author":"Sanders","year":"2015","journal-title":"Genome Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1038\/s41598-017-01519-4","article-title":"An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations","volume":"7","author":"Stayner","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.ajhg.2016.07.009","article-title":"Mutations in CEP78 cause cone-rod dystrophy and hearing loss associated with primary-cilia defects","volume":"99","author":"Nikopoulos","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.1093\/hmg\/ddx347","article-title":"A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies","volume":"26","author":"Srivastava","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Garanto, A., van Beersum, S.E.C., Peters, T.A., Roepman, R., Cremers, F.P.M., and Collin, R.W.J. (2013). Unexpected CEP290 mRNA splicing in a humanized knock-in mouse model for leber congenital amaurosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079369"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1091\/mbc.e04-07-0586","article-title":"Flagellar length control system: Testing a simple model based on intraflagellar transport and turnover","volume":"16","author":"Marshall","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1080\/13816810902744621","article-title":"PRPF31 alternative splicing and expression in human retina","volume":"30","author":"Tanackovic","year":"2009","journal-title":"Ophthalmic Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/5\/368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:51:53Z","timestamp":1760187113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/5\/368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,14]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["genes10050368"],"URL":"https:\/\/doi.org\/10.3390\/genes10050368","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,14]]}}}