Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

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The authors thank the patients and their families for their cooperation and interest in the study; M.T. Toh and Y.T. Koh for technical assistance; W.I. Goh of the Institute of Medical Biology's Microscopy Unit for assistance with super-resolution microscopy; J. Lefevre and N. Hamilton for advice on statistical analyses; and C. Cortés, M. Pitt, F. Olsson, L. Zhao, L. Wilkinson and P. Karaith Oliva for assistance, insightful discussion and advice. The authors also thank C. Has (University Medical Center Freiburg) for kindly providing control fibroblasts; S. Somlo, M. Ma and K. Dong (Yale University) for Pkd1- and Pkd2-mutant cells; L. Lei (Nanyang Technological University) for the RPE-1 cell line stably expressing Arl13b–GFP; L. Pelletier (Lunenfeld-Tanenbaum Research Institute) for basal-body and transition-zone-protein cDNA clones; and R. Witzgall (Institute for Molecular and Cellular Anatomy, University of Regensburg), G. Wu (Center of Translational Cancer Research and Therapy, Beijing) and R. Rohatgi (Stanford University) for antibodies. We also thank the staff of the University of Queensland (UQ) QBP animal house for assistance with mouse husbandry and the Australian Phenomics Facility for maintaining mice throughout the screen. Confocal microscopy at UQ was carried out at the Institute for Molecular Bioscience Dynamic Imaging Facility for Cancer Biology, which is funded through the generous support of the Australian Cancer Research Foundation. We also acknowledge the Australian Microscopy & Microanalysis Facility (AMMRF) at the Centre for Microscopy and Microanalysis at UQ. M.H., S.N., V.F. and C.B. are supported as employees of Bioscientia/Sonic Healthcare; C.W. was supported as a recipient of a University of Queensland Vice-Chancellor's Senior Research Fellowship; and S.R. is supported as a Senior Principal Investigator at the Institute of Molecular and Cell Biology, Singapore. M.H.L. is supported as a Senior Principal Research Fellow of the Australian National Health and Medical Research Council (NHMRC). F.H. is supported as the Warren E. Grupe Professor. This work was supported by grants from the German Research Fund (DFG) to K.Z. and C.B., the DFG Collaborative Research Centre (SFB) KIDGEM 1140 and the Federal Ministry of Education and Research (BMBF, 01GM1515C) to C.B., the Australian NHMRC (APP1045464) to C.W., the National Institutes of Health NIH (DK068306) to F.H. and the Agency for Science, Technology and Research (A*STAR) of Singapore to W.H. and S.R. This paper is dedicated to the memory of Markus Nauck, who recently passed away.

Author information

Author notes

    • Vicki Metzis
    • , Shubha Vij
    • , Melissa H Little
    •  & Peter Papathanasiou

    Present addresses: Francis Crick Institute, London, UK (V.M.), Temasek Life Sciences Laboratory Limited, National University of Singapore, Singapore (S.V.), Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia (M.H.L.) and Department of Materials, Imperial College London, London, UK (P.P.).

    • Hao Lu
    • , Maria C Rondón Galeano
    •  & Elisabeth Ott

    These authors contributed equally to this work.

    • Carol Wicking
    •  & Carsten Bergmann

    These authors jointly directed this work.


  1. Institute of Molecular and Cell Biology, Singapore.

    • Hao Lu
    • , P Jaya Kausalya
    • , Shang Yew Tay
    • , Shubha Vij
    • , Walter Hunziker
    •  & Sudipto Roy
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

    • Maria C Rondón Galeano
    • , Geraldine Kaeslin
    • , Vicki Metzis
    • , Andrew D Courtney
    • , Melissa H Little
    • , Andrew C Perkins
    •  & Carol Wicking
  3. Department of Medicine IV, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

    • Elisabeth Ott
    • , Carina Kramer
    • , Daniel Epting
    •  & Carsten Bergmann
  4. Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.

    • Nadina Ortiz-Brüchle
    • , Nadescha Hilger
    • , Klaus Zerres
    •  & Carsten Bergmann
  5. Center for Human Genetics, Bioscientia, Ingelheim, Germany.

    • Milan Hiersche
    • , Steffen Neuber
    • , Valeska Frank
    •  & Carsten Bergmann
  6. John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.

    • Robert Tunningley
    • , Belinda Whittle
    •  & Peter Papathanasiou
  7. Division of Pediatric Nephrology, University Children's Hospital Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.

    • Elke Wühl
  8. Department of Pediatric Nephrology, University Children's Hospital Essen, Essen, Germany.

    • Udo Vester
  9. Institute of Pathology, MHH University Medical School Hannover, Hannover, Germany.

    • Björn Hartleben
  10. Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, Queensland, Australia.

    • Andrew C Perkins
  11. Institute of Medical Biology, A*STAR, Singapore.

    • Graham D Wright
  12. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Walter Hunziker
  13. Singapore Eye Research Institute, Singapore.

    • Walter Hunziker
  14. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Heon Yung Gee
    •  & Friedhelm Hildebrandt
  15. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.

    • Heon Yung Gee
  16. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.

    • Edgar A Otto
  17. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Sudipto Roy
  18. Department of Biological Sciences, National University of Singapore, Singapore.

    • Sudipto Roy


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H.L., P.J.K., S.Y.T., S.V. and S.R. performed the zebrafish mutant and morphant analyses, protein interaction studies, localization experiments with human fibroblasts and validation of antibodies to PCs. W.H. supervised the protein interaction studies. E.O., C.K. and D.E. performed the zebrafish morpholino analyses. M.C.R.G., G.K., V.M. and A.D.C. performed the mouse analyses, and M.C.R.G. and G.K. performed the localization experiments with mouse cells. R.T., P.P. and A.C.P. performed the screen that identified the mouse mutant, and B.W. was involved in mapping and identifying the mouse mutation. G.D.W. performed the super-resolution microscopy experiments. M.H.L. assisted with design and analysis of mouse kidney experiments. N.O.-B., N.H., V.F. and S.N. performed the human mutation analysis. S.N., V.F., M.H., H.Y.G., E.A.O., F.H. and C.B. carried out the WES data processing and analyses. S.N., V.F., E.W., U.V., H.Y.G., K.Z., F.H. and C.B. recruited and clinically characterized the study subjects and collected samples. B.H. performed histologic evaluation of the data. S.R., C.W. and C.B. conceived the project, designed and supervised the experiments, analyzed and interpreted the data and wrote the manuscript. All authors reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sudipto Roy or Carol Wicking or Carsten Bergmann.

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    Supplementary Table 2

    DZIP1L Y2H screen.

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