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.

Department of Biosciences and Nutrition Karolinska Institutet 14183 Huddinge Sweden

Department of Biosciences and Nutrition Karolinska Institutet 14183 Huddinge Sweden; Molecular Neurology Research Program University of Helsinki and Folkhälsan Institute of Genetics 00014 Helsinki Finland; Science for Life Laboratory Karolinska Institutet 171 21 Solna Sweden

Department of Gastroenterology and Hepatology Radboud UMC P O Box 9101 6500 HB Nijmegen the Netherlands

Department of Genetics Yale University School of Medicine New Haven CT 06510 USA; Howard Hughes Medical Institute Chevy Chase MD 20815 USA

Department of Histopathology Great Ormond Street Hospital London WC1N3JH UK

Department of Medicine Boston Children's Hospital Harvard Medical School Boston MA 02115 USA

Department of Medicine Boston Children's Hospital Harvard Medical School Boston MA 02115 USA; Howard Hughes Medical Institute Chevy Chase MD 20815 USA

Department of Nephrology and Hypertension University Medical Center Utrecht 3584CX Utrecht the Netherlands

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Ke Karlovu 2 Prague 2 128 08 Czech Republic

Department of Pediatrics and Communicable Diseases University of Michigan Ann Arbor MI 48109 USA

Department of Physiology and Neurobiology University of Connecticut Storrs CT 06269 USA

Division of Nephrology and Hypertension Mayo Clinic Rochester MN 55905 USA

Inserm U574 and Department of Genetics Paris 5 University Necker Hospital 75015 Paris France

Institute of Human Genetics University Hospital RWTH Aachen 52074 Aachen Germany

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital 600 University Avenue Toronto Ontario M5G 1X5 Canada; Department of Molecular Genetics University of Toronto Toronto Ontario M5S 1A8 Canada

Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda MD 20892 USA

University College London Institute of Child Health and Pediatric Nephrology Great Ormond Street Hospital London WC1N3JH UK

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