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

 Hao Lu  ;  Maria C. Rondón Galeano  ;  Elisabeth Ott  ;  Geraldine Kaeslin  ;  P. Jaya Kausalya  ;  Carina Kramer  ;  Nadina Ortiz-Brüchle  ;  Nadescha Hilger  ;  Vicki Metzis  ;  Milan Hiersche  ;  Shang Yew Tay  ;  Robert Tunningley  ;  Shubha Vij  ;  Andrew D. Courtney  ;  Belinda Whittle  ;  Elke Wühl  ;  Udo Vester  ;  Björn Hartleben  ;  Steffen Neuber  ;  Valeska Frank  ;  Melissa H. Little  ;  Daniel Epting  ;  Peter Papathanasiou  ;  Andrew C. Perkins  ;  Graham D. Wright  ;  Walter Hunziker  ;  Heon Yung Gee  ;  Edgar A. Otto  ;  Klaus Zerres  ;  Friedhelm Hildebrandt  ;  Sudipto Roy  ;  Carol Wicking  ;  Carsten Bergmann 
 NATURE GENETICS, Vol.49(7) : 1025-1034, 2017 
Journal Title
Issue Date
Abnormalities, Multiple/embryology ; Abnormalities, Multiple/genetics ; Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/physiology ; Animals ; Centrioles/metabolism ; Chromosomes, Human, Pair 3/genetics ; Cilia/metabolism ; Consanguinity ; Disease Models, Animal ; Embryo, Nonmammalian/abnormalities ; Female ; Gene Knockdown Techniques ; Genetic Linkage ; Humans ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Pedigree ; Polycystic Kidney, Autosomal Recessive/embryology ; Polycystic Kidney, Autosomal Recessive/genetics ; Protein Transport ; Septins/metabolism ; TRPP Cation Channels/metabolism ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish Proteins/deficiency ; Zebrafish Proteins/genetics ; Zebrafish Proteins/physiology
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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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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