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

摘要

Nephronophtisis (NPH) is a kidney ciliopathy often associatedwith extra-renal defects and for which 12 genes(NPHP1-12) have been identified. NPHP1 and NPHP4control the ciliary access at the transition zone and thevelocity of some intraflagellar transport (IFT)/BBS proteinsin C.elegans. Recently, in a collaborative effort, we haveidentified, in families with isolated NPH, mutations inTTC21B as well as in WDR19, which encode the retrogradeIFT-A proteins IFT139 and IFT144, respectively. Byciliome sequencing of 1600 candidate genes from 14 NPHpatients followed by Sanger sequencing of a cohort of 52patients, we have found respectively 8 and 7 patients carryingpathogenic missense mutations in genes coding IFTAproteins, including WDR35, TTC21B and IFT140,which could partially affect their function. Together, theseresults indicate that IFT-A are involved in nephronophtisis.Moreover, alteration of cilia length was observed inpatient kidney, Nphp4-/- mice kidney tubules and NPHP1or NPHP4 knockdown IMCD3 cell lines. In these cells,primary cilia present swellings at the distal region accompaniedby an accumulation of IFT-B at the base and thetip, similar to what was observed in IFT-A mutants, suggestinga possible alteration of retrograde transport. Additionally,ARL13B, a small GTPase required for propercilium shape and IFT stability, is absent along the axonemeof NPHP4-KD-IMCD cells. By controlling the entryof ciliary components at the transition zone, NPHP1 andNPHP4 may modulate IFT-A cargos thus participating inthe same pathway (i.e. Wnt/PCP), alteration of whichwould lead to renal lesions observed in nephronophthisis.