PUBLICATION
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease
- Authors
- Lu, H., Galeano, M.C.R., Ott, E., Kaeslin, G., Kausalya, P.J., Kramer, C., Ortiz-Brüchle, N., Hilger, N., Metzis, V., Hiersche, M., Tay, S.Y., Tunningley, R., Vij, S., Courtney, A.D., Whittle, B., Wühl, E., Vester, U., Hartleben, B., Neuber, S., Frank, V., Little, M.H., Epting, D., Papathanasiou, P., Perkins, A.C., Wright, G.D., Hunziker, W., Gee, H.Y., Otto, E.A., Zerres, K., Hildebrandt, F., Roy, S., Wicking, C., Bergmann, C.
- ID
- ZDB-PUB-170523-4
- Date
- 2017
- Source
- Nature Genetics 49: 1025–1034 (Journal)
- Registered Authors
- Bergmann, Carsten, Epting, Daniel, Kramer, Carina, Ott, Elisabeth B., Perkins, Andrew, Roy, Sudipto, Tay, Shang Yew
- Keywords
- Genetic linkage study, Genetic testing, Polycystic kidney disease
- MeSH Terms
-
- 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
- PubMed
- 28530676 Full text @ Nat. Genet.
Citation
Lu, H., Galeano, M.C.R., Ott, E., Kaeslin, G., Kausalya, P.J., Kramer, C., Ortiz-Brüchle, N., Hilger, N., Metzis, V., Hiersche, M., Tay, S.Y., Tunningley, R., Vij, S., Courtney, A.D., Whittle, B., Wühl, E., Vester, U., Hartleben, B., Neuber, S., Frank, V., Little, M.H., Epting, D., Papathanasiou, P., Perkins, A.C., Wright, G.D., Hunziker, W., Gee, H.Y., Otto, E.A., Zerres, K., Hildebrandt, F., Roy, S., Wicking, C., Bergmann, C. (2017) Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nature Genetics. 49:1025–1034.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping