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

Markus Schueler, Daniela A. Braun, Gayathri Chandrasekar, Heon Yung Gee, Timothy D. Klasson, Jan Halbritter, Andrea Bieder, Jonathan D. Porath, Rannar Airik, Weibin Zhou, Joseph J. Loturco, Alicia Che, Edgar A. Otto, Detlef Böckenhauer, Neil J. Sebire, Tomas Honzik, Peter C. Harris, Sarah J. Koon, Meral Gunay-Aygun, Sophie SaunierKlaus Zerres, Nadina Ortiz Bruechle, Joost P.H. Drenth, Laurence Pelletier, Isabel Tapia-Páez, Richard P. Lifton, Rachel H. Giles, Juha Kere, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)81-92
Number of pages12
JournalAmerican journal of human genetics
Volume96
Issue number1
DOIs
StatePublished - Jan 8 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Schueler, M., Braun, D. A., Chandrasekar, G., Gee, H. Y., Klasson, T. D., Halbritter, J., Bieder, A., Porath, J. D., Airik, R., Zhou, W., Loturco, J. J., Che, A., Otto, E. A., Böckenhauer, D., Sebire, N. J., Honzik, T., Harris, P. C., Koon, S. J., Gunay-Aygun, M., ... Hildebrandt, F. (2015). DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. American journal of human genetics, 96(1), 81-92. https://doi.org/10.1016/j.ajhg.2014.12.002