Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
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NCBI Reference Sequence
We are grateful to all patients and family members for their participation. We thank A. Sammarco, C. Engel, B. Müller, L. Schomas, S. Bräg and M. Klein for excellent technical assistance, the staff of the Life Imaging Center (LIC) in the Center for Systems Biology, Albert-Ludwigs-University Freiburg for excellent confocal microscopy resources and the support in image recording and analysis, and U. Lanner and E. Haaf of the proteomics core facility. We thank N. Katsanis and J. Willer (Duke University) for providing us with expression constructs for NEK7 and INVS. We thank K. Coene for her help in generating affinity proteomics data for NEK8. We thank E. Jones for making the 3G8 and 4A6 antibodies available through the European Xenopus stock centre. V.F., T.E., H.J.B. and C. Bergmann are employees of Bioscientia, a member of Sonic Healthcare. D.B. is a Higher Education Funding Council for England (HEFCE) Clinical Reader and is supported by Kids Kidney Research. A.K.-Z., G.W., E.W.K., F.G., T.B.H. and S.S.L. are supported by the Deutsche Forschungsgemeinschaft (DFG; KFO 201). E.W.K. is supported by the DFG (KU 1504). C. Boehlke is supported by the Else-Kröner-Fresenius Stiftung. G.W. and T.B.H. are supported by the Excellence Initiative of the German Federal and State Governments (EXC 294-BIOSS). M.U., R.R. and G.W. are supported by the European Community's Seventh Framework Programme (grant agreement 241955, SYSCILIA). R.R. is supported by the Netherlands Organisation for Scientific Research (NWO Vidi-91786396 and Vici-016.130.664). K.B. and M.U. are supported by the European Community's Seventh Framework Programme under grant agreement 278568, PRIMES. This study was supported in part by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School) and by grants from the Agence Nationale de la Recherche to S.S. (R09087KS and RPV11012KK) and the Fondation pour la Recherche Médicale (DEQ20071210558). This research was supported by grants from the US National Institutes of Health to F.H. (DK068306 and DK090917). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G.L. Huetwell Professor. C. Bergmann received support from the DFG (BE 3910/4-1, ZE 205/14-1 and SFB/TRR57), the Deutsche Nierenstiftung and the PKD Foundation.
Supplementary Table 1
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Biology of the Cell (2019)