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3D renal modeling classifies BHD as a ciliopathy, possibly responsive to treatment with PTC124

Ciliopathy is a general term applied to diseases that originate from ciliary dysfunction, which often coincide with renal cyst development. Any syndrome displaying renal cysts, such as folliculin (FLCN) in Birt-Hogg-Dube (BHD) syndrome, might therefore be suspected as a novel ciliopathy. Indeed, FLCN localizes to the primary cilium. To study ciliopathies in detail, we set up a renal 3D culture system using IMCD3 cells that physiologically mimick polarized renal tubuli. SiFlcn was essayed in this system, identifying several affected processes; 1) Reduction of ciliation in vitro and in vivo. 2) Increase in cell volume. 3) Increase of mis-oriented cell divisions. These results suggest Flcn functions in cilia stability/ciliogenesis and planar cell polarity (PCP) regulation. PCP signaling is a form of non-canonical Wnt signaling subjected to ciliary regulation Accordingly, whereas β-catenin is normally present in the axoneme, this is never observed upon Flcn depletion and Wnt signaling appears increased as downstream effector Axin2 is stabilized. This suggests a switch from PCP to canonical signaling. Notably, upon ectopic GFP-FLCN expression, but not the non-functional allele p.L508R, cilia become stabilized, accompanied by an accumulation of both GFP-FLCN and β-catenin in the cilium. The second most common mutant FLCN allele is p.T463X; forced read-through with pharmaceutical agent PTC124, targeting nonsense-mediated decay, was tested and showed a robust response as protein expression appears fully restored. We suggest that BHD regulates ciliary function in a 3D polarized cell assay, and PTC124 might be a simple therapy for the second most frequent allele in BHD carriers.

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Correspondence to S Basten.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Basten, S., Haidari, K., Slaats, G. et al. 3D renal modeling classifies BHD as a ciliopathy, possibly responsive to treatment with PTC124. Cilia 1 (Suppl 1), P82 (2012).

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