Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease PMID: 28530676

ADC Targets in Oncology

2026-04-10

Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease

Nat Genet. 2017 Jul;49(7):1025-1034. doi: 10.1038/ng.3871.

Hao Lu ¹ , Maria C Rondón Galeano ² , Elisabeth Ott ³ , Geraldine Kaeslin ² , P Jaya Kausalya ¹ , Carina Kramer ³ , Nadina Ortiz-Brüchle ⁴ , Nadescha Hilger ⁴ , Vicki Metzis ² , Milan Hiersche ⁵ , Shang Yew Tay ¹ , Robert Tunningley ⁶ , Shubha Vij ¹ , Andrew D Courtney ² , Belinda Whittle ⁶ , Elke Wühl ⁷ , Udo Vester ⁸ , Björn Hartleben ⁹ , Steffen Neuber ⁵ , Valeska Frank ⁵ , Melissa H Little ² , Daniel Epting ³ , Peter Papathanasiou ⁶ , Andrew C Perkins ² ¹⁰ , Graham D Wright ¹¹ , Walter Hunziker ¹ ¹² ¹³ , Heon Yung Gee ¹⁴ ¹⁵ , Edgar A Otto ¹⁶ , Klaus Zerres ⁴ , Friedhelm Hildebrandt ¹⁴ , Sudipto Roy ¹ ¹⁷ ¹⁸ , Carol Wicking ² , Carsten Bergmann ³ ⁴ ⁵

Affiliations

1. Institute of Molecular and Cell Biology, Singapore.
2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
3. Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4. Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.
5. Center for Human Genetics, Bioscientia, Ingelheim, Germany.
6. John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
7. Division of Pediatric Nephrology, University Children's Hospital Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
8. Department of Pediatric Nephrology, University Children's Hospital Essen, Essen, Germany.
9. Institute of Pathology, MHH University Medical School Hannover, Hannover, Germany.
10. Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, Queensland, Australia.
11. Institute of Medical Biology, A*STAR, Singapore.
12. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
13. Singapore Eye Research Institute, Singapore.
14. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
15. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
16. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
17. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
18. Department of Biological Sciences, National University of Singapore, Singapore.

Abstract

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.