title: DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling.
abstract: 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.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chandrasekar
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Klasson
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bieder
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: LoTurco
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Che
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.affiliation: University College London, Institute of Child Health and Pediatric Nephrology, Great Ormond Street Hospital, London WC1N3JH, UK.
authors.forename: Detlef
authors.initials: D
authors.lastname: Böckenhauer
authors.affiliation: Department of Histopathology, Great Ormond Street Hospital, London WC1N3JH, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzik
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Koon
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
authors.affiliation: Inserm U574 and Department of Genetics, Paris 5 University, Necker Hospital, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.affiliation: Institute of Human Genetics, University Hospital, RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.affiliation: Institute of Human Genetics, University Hospital, RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Nadina Ortiz
authors.initials: NO
authors.lastname: Bruechle
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud UMC, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Pelletier
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tapia-Páez
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: 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. Electronic address: juha.kere@ki.se.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002923:Cilia / Q000235:genetics / Q000473:pathology; D019295:Computational Biology; D000072261:Dishevelled Proteins; D005091:Exons; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510451:DCDC2 protein, human; C570668:DCDC2 protein, mouse; D000072261:Dishevelled Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D051176:beta Catenin