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

Nat Genet. 2017 Jul;49(7):1025-1034. Epub 2017 May 22
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 10 , Graham D Wright 11 , Walter Hunziker 12 , Heon Yung Gee 13 , Edgar A Otto 14 , Klaus Zerres 4 , Friedhelm Hildebrandt 15 , Sudipto Roy 16 , Carol Wicking 2 , Carsten Bergmann 5
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 10 , Graham D Wright 11 , Walter Hunziker 12 , Heon Yung Gee 13 , Edgar A Otto 14 , Klaus Zerres 4 , Friedhelm Hildebrandt 15 , Sudipto Roy 16 , Carol Wicking 2 , Carsten Bergmann 5
+ et al

[No authors listed]

Author information
  • 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 Singapore Eye Research Institute, Singapore.
  • 13 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 14 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
  • 15 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 16 Department of Biological Sciences, National University of Singapore, Singapore.

摘要


Autosomal recessive polycystic kidney disease 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 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 is not a homogeneous disorder and further establish DZIP1L as a second gene involved in duanyu37KD pathogenesis.