2. Academic Validation
  3. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling

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

  • Am J Hum Genet. 2015 Jan 8;96(1):81-92. doi: 10.1016/j.ajhg.2014.12.002.
Markus Schueler 1,  Daniela A Braun 1,  Gayathri Chandrasekar 2,  Heon Yung Gee 1,  Timothy D Klasson 3,  Jan Halbritter 1,  Andrea Bieder 2,  Jonathan D Porath 1,  Rannar Airik 1,  Weibin Zhou 4,  Joseph J LoTurco 5,  Alicia Che 5,  Edgar A Otto 4,  Detlef Böckenhauer 6,  Neil J Sebire 7,  Tomas Honzik 8,  Peter C Harris 9,  Sarah J Koon 9,  Meral Gunay-Aygun 10,  Sophie Saunier 11,  Klaus Zerres 12,  Nadina Ortiz Bruechle 12,  Joost P H Drenth 13,  Laurence Pelletier 14,  Isabel Tapia-Páez 2,  Richard P Lifton 15,  Rachel H Giles 3,  Juha Kere 16,  Friedhelm Hildebrandt 17
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
PMID: 25557784 DOI: 10.1016/j.ajhg.2014.12.002
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.

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