Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC.
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We are grateful to families and study individuals for their contribution. We would like to thank Milan Elleder and Helena Hůlkova (Institute for Inherited Metabolic Disorders) for histological preparation of liver biopsy specimen. We thank the zebrafish core facility, Karolinska Institutet for providing zebrafish embryos. We thank Kjell Hultenby, Eva Blomen, and Sally Cheung for technical support. We thank the Live Cell Imaging unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet for their support. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to P.C.H. (DK090728, DK059597), to R.A. (DK099434), and by the CIHR to L.P. (MOP130507). H.Y.G. is supported by the NephCure Foundation and by the ASN Foundation for Kidney Research. T.H. was supported by General University Hospital program RVO-VFN 64165/2012. This work was in part supported by grants to J.K. from Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Biosciences, the Centre for Innovative Medicine, and Jonasson donation to the School of Technology and Health, Kungliga Tekniska Högskolan, Swedish Brain Foundation (Hjärnfonden) and Swedish Brain Foundations postdoc fellowship award to G.C., from the European Union Framework Programmes 241955 “SYSCILIA” and 305608 “EURenOmics” as well as the Dutch Kidney Foundation grants CP11.18 “KOUNCIL”/13A3D103 to R.H.G., and from the Deutsche Forschungs–gemeinschaft to K.Z. (ZE 205/14-1). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor.
© 2015 The American Society of Human Genetics.
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