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Targeted exon skipping rescues ciliary protein composition defects in Joubert syndrome patient fibroblasts

Lookup NU author(s): Dr Elisa MolinariORCiD, Dr Simon RamsbottomORCiD, Dr Shalabh Srivastava, Philip Booth, Sumaya Alkanderi, Laura Devlin, Dr Kathryn White, Dr Colin Miles, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019, The Author(s).Joubert syndrome (JBTS) is an incurable multisystem ciliopathy syndrome. The most commonly mutated gene in JBTS patients with a cerebello-retinal-renal phenotype is CEP290 (alias JBTS5). The encoded CEP290 protein localises to the proximal end of the primary cilium, in the transition zone, where it controls ciliary protein composition and signalling. We examined primary cilium structure and composition in fibroblast cells derived from homozygous and compound heterozygous JBTS5 patients with nonsense mutations in CEP290 and show that elongation of cilia, impaired ciliogenesis and ciliary composition defects are typical features in JBTS5 cells. Targeted skipping of the mutated exon c.5668 G > T using antisense oligonucleotide (ASO) therapy leads to restoration of CEP290 protein expression and functions at the transition zone in homozygous and compound heterozygous JBTS5 cells, allowing a rescue of both cilia morphology and ciliary composition. This study, by demonstrating that targeted exon skipping is able to rescue ciliary protein composition defects, provides functional evidence for the efficacy of this approach in the treatment of JBTS.

Publication metadata

Author(s): Molinari E, Ramsbottom SA, Srivastava S, Booth P, Alkanderi S, McLafferty SM, Devlin LA, White K, Gunay-Aygun M, Miles CG, Sayer JA

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 25/07/2019

Acceptance date: 12/07/2019

Date deposited: 29/08/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/s41598-019-47243-z

PubMed id: 31346239


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