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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.
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
URL: https://doi.org/10.1093/hmg/ddx347
DOI: 10.1093/hmg/ddx347
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