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This article is part of the supplement: Proceedings of the First International Cilia in Development and Disease Scientific Conference (2012)

Open Access Poster presentation

Alteration of nephrocystins and IFT-A proteins causes similar ciliary phenotypes leading to Nephronophthisis

S Saunier1*, AA Bizet1, F Silbermann1, E Filhol1, T Blisnick2, A Henneveu3, E Montenont1, I Perrault4, C Boyle-Feysot5, J-M Rozet4, P Bastin2, HH Arts6, C Antignac1 and AR Benmerah3

Author Affiliations

1 Inserm U983, France

2 Pasteur Institute, CNRS UMR2581, France

3 Inserm U1016, Cochin Institute, France

4 Inserm U781, France

5 Fondation Imagine, Paris, France

6 Radboud University Nijmegen Medical Center, the Netherlands

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Cilia 2012, 1(Suppl 1):P99  doi:10.1186/2046-2530-1-S1-P99

The electronic version of this article is the complete one and can be found online at: http://www.ciliajournal.com/content/1/S1/P99


Published:16 November 2012

© 2012 Saunier et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Poster presentation

Nephronophtisis (NPH) is a kidney ciliopathy often associated with extra-renal defects and for which 12 genes (NPHP1-12) have been identified. NPHP1 and NPHP4 control the ciliary access at the transition zone and the velocity of some intraflagellar transport (IFT)/BBS proteins in C.elegans. Recently, in a collaborative effort, we have identified, in families with isolated NPH, mutations in TTC21B as well as in WDR19, which encode the retrograde IFT-A proteins IFT139 and IFT144, respectively. By ciliome sequencing of 1600 candidate genes from 14 NPH patients followed by Sanger sequencing of a cohort of 52 patients, we have found respectively 8 and 7 patients carrying pathogenic missense mutations in genes coding IFT-A proteins, including WDR35, TTC21B and IFT140, which could partially affect their function. Together, these results indicate that IFT-A are involved in nephronophtisis. Moreover, alteration of cilia length was observed in patient kidney, Nphp4-/- mice kidney tubules and NPHP1 or NPHP4 knockdown IMCD3 cell lines. In these cells, primary cilia present swellings at the distal region accompanied by an accumulation of IFT-B at the base and the tip, similar to what was observed in IFT-A mutants, suggesting a possible alteration of retrograde transport. Additionally, ARL13B, a small GTPase required for proper cilium shape and IFT stability, is absent along the axoneme of NPHP4-KD-IMCD cells. By controlling the entry of ciliary components at the transition zone, NPHP1 and NPHP4 may modulate IFT-A cargos thus participating in the same pathway (i.e. Wnt/PCP), alteration of which would lead to renal lesions observed in nephronophthisis.