Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 96, Issue 1, Pages 81-92Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.12.002
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Funding
- Live Cell Imaging unit/Nikon Center of Excellence
- Department of Biosciences and Nutrition, Karolinska Institutet
- National Institutes of Health [DK1069274, DK1068306, DK064614, DK090728, DK059597, DK099434]
- CIHR [MOP130507]
- NephCure Foundation
- ASN Foundation for Kidney Research
- General University Hospital [RVO-VFN 64165/2012]
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- Centre for Biosciences
- Centre for Innovative Medicine
- Kungliga Tekniska Hogskolan
- Swedish Brain Foundation (Hjarnfonden)
- Swedish Brain Foundation
- European Union [241955, 305608]
- Dutch Kidney Foundation [CP11.18 KOUNCIL/13A3D103]
- Deutsche Forschungs-gemeinschaft [ZE 205/14-1]
- Jonasson
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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 beta-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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