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Am J Hum Genet. 2015 Jan 8;96(1):81-92. doi: 10.1016/j.ajhg.2014.12.002. Epub 2014 Dec 31.

DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling.

Author information

1
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
3
Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands.
4
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
6
University College London, Institute of Child Health and Pediatric Nephrology, Great Ormond Street Hospital, London WC1N3JH, UK.
7
Department of Histopathology, Great Ormond Street Hospital, London WC1N3JH, UK.
8
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.
9
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
10
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
11
Inserm U574 and Department of Genetics, Paris 5 University, Necker Hospital, 75015 Paris, France.
12
Institute of Human Genetics, University Hospital, RWTH Aachen, 52074 Aachen, Germany.
13
Department of Gastroenterology and Hepatology, Radboud UMC, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
14
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.
15
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
16
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.
17
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.

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.

PMID:
25557784
PMCID:
PMC4289677
DOI:
10.1016/j.ajhg.2014.12.002
[Indexed for MEDLINE]
Free PMC Article

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