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A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies

Lookup NU author(s): Dr Shalabh Srivastava, Dr Simon RamsbottomORCiD, Dr Elisa MolinariORCiD, Sumaya Alkanderi, Professor Andrew FilbyORCiD, 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).


Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganised primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinases (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognised convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.

Publication metadata

Author(s): Srivastava S, Ramsbottom SA, Molinari E, Alkanderi S, Filby A, White K, Henry C, Saunier S, Miles CG, Sayer JA

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2017

Volume: 26

Issue: 23

Pages: 4657-4667

Print publication date: 01/12/2017

Online publication date: 11/09/2017

Acceptance date: 30/08/2017

Date deposited: 11/09/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddx347


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Funder referenceFunder name
Kidney Research UK