Journal Article

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

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

2017

Overview

Sudipto Roy, Carol Wicking, Carsten Bergmann and colleagues report that mutations in DZIP1L cause autosomal recessive polycystic kidney disease (ARPKD). Through studies of mouse and zebrafish models of DZIP1L loss of function, the authors demonstrate that DZIP1L is required for proper function of the periciliary diffusion barrier. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/207 / 631/208/2489/1512 / 692/699/1585/1589 / Abnormalities, Multiple - embryology / Abnormalities, Multiple - genetics / Adaptor Proteins, Signal Transducing - deficiency / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - physiology / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer Research / Centrioles - metabolism / Chromosomes, Human, Pair 3 - genetics / Cilia - metabolism / Consanguinity / Disease Models, Animal / Embryo, Nonmammalian - abnormalities / Female / Gene Function / Gene Knockdown Techniques / Gene mutation / Genetic aspects / Genetic Linkage / Human Genetics / Humans / Male / Membrane Proteins - metabolism / Mice / Mice, Inbred C57BL / Pedigree / Polycystic kidney disease / 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