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