Publication Type:Journal Article
Source:Nat Genet, Volume 49, Issue 7, p.1025-1034 (2017)
Keywords:Abnormalities, Multiple, Adaptor Proteins, Signal Transducing, Animals, Centrioles, Chromosomes, Human, Pair 3, Cilia, Consanguinity, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Knockdown Techniques, Genetic Linkage, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Pedigree, Polycystic Kidney, Autosomal Recessive, Protein Transport, Septins, TRPP Cation Channels, Zebrafish, Zebrafish Proteins
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.