title: Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia.
abstract: Nephronophthisis (NPHP) is a hereditary cystic kidney disorder that causes renal failure in children and young adults and can be associated with various extrarenal disorders, including retinitis pigmentosa. Six NPHP genes, whose functions are disrupted by autosomal recessive mutations in patients with NPHP, have been identified. The majority of patients with NPHP carry homozygous deletions of NPHP1 encoding nephrocystin. Previous data indicate that nephrocystin forms a complex at cell junctions and focal adhesions. Here, it is shown that nephrocystin specifically localizes at the ciliary base to the transition zone of renal and respiratory cilia and to photoreceptor connecting cilia. During in vitro ciliogenesis of primary human respiratory epithelial cells, nephrocystin can be detected first with a diffuse cytoplasmic localization as soon as cell polarization starts, and translocates to the transition zone when cilia are formed. In columnar respiratory cells, nephrocystin is attached tightly to the axonemal structure of the transition zone at a region that contains the calcium-sensitive cilia autotomy site. In patients with homozygous NPHP1 deletions, nephrocystin is absent from the entire respiratory cell, including the transition zone, which might be of interest for future diagnostic approaches. Cilia formation is not altered in primary nephrocystin-deficient respiratory cells, which is consistent with previous findings obtained for the Caenorhabditis elegans ortholog. In addition, it is shown that the localization pattern of intraflagellar transport proteins and nephrocystin differs, suggesting distinct functional roles. In conclusion, nephrocystin deficiency or dysfunction at the transition zone of renal monocilia and the photoreceptor connecting cilium might explain renal failure and retinal degeneration that are observed in patients with NPHP1.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.forename: Judit
authors.initials: J
authors.lastname: Horvath
authors.forename: Christian
authors.initials: C
authors.lastname: von Schnakenburg
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: Julia
authors.initials: J
authors.lastname: Thumfart
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pazour
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Hanswalter
authors.initials: H
authors.lastname: Zentgraf
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002923:Cilia / Q000502:physiology*; D003598:Cytoskeletal Proteins; D004285:Dogs; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000503:physiopathology*; D008565:Membrane Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D009297:Nasal Mucosa / Q000648:ultrastructure; D010786:Photoreceptor Cells / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D011506:Proteins