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

Nat Genet. 2017 Jul;49(7):1025-1034. doi: 10.1038/ng.3871. Epub 2017 May 22.

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.

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

Substances

  • Adaptor Proteins, Signal Transducing
  • DZIP1L protein, human
  • DZIP1L protein, mouse
  • DZIP1L protein, zebrafish
  • Membrane Proteins
  • TRPP Cation Channels
  • Zebrafish Proteins
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein
  • SEPTIN2 protein, human
  • Septins