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ZIRC
ZFIN ID: ZDB-PUB-170523-4
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease
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.
Date: 2017
Source: Nature Genetics 49: 1025–1034 (Journal)
Registered Authors: 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.
FIGURES
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.
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