title: Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation.
abstract: Null mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-Løken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5-knockout mice by placing a β-Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5-/-mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis. Outer segment transmembrane protein accumulation in Nphp5-/-endoplasmic reticulum was evident as early as postnatal day (P)6. EGFP-CETN2, a centrosome and transition zone marker, identified basal bodies in Nphp5-/-photoreceptors, but without fully developed transition zones. Ultrastructure of P6 and 10 Nphp5-/-photoreceptors revealed aberrant transition zones of reduced diameter. Nphp5-/-photoreceptor degeneration was complete at 1 mo of age but was delayed significantly in Nphp5-/-;Nrl-/-(cone only) retina. Nphp5-/-mouse embryonic fibroblast developed normal cilia, and Nphp5-/-kidney histology at 1 yr of age showed no significant pathology. Results establish that nephrocystin-5 is essential for photoreceptor outer segment formation but is dispensable for kidney and mouse embryonic fibroblast ciliary formation.-Ronquillo, C. C., Hanke-Gogokhia, C., Revelo, M. P., Frederick, J. M., Jiang, L., Baehr, W. Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation.
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA.
authors.forename: Cecinio C
authors.initials: CC
authors.lastname: Ronquillo
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Hanke-Gogokhia
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Monica P
authors.initials: MP
authors.lastname: Revelo
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA; li.jiang@hsc.utah.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA; Department of Neurobiology and Anatomy, University of Utah Health Science Center, Salt Lake City, Utah, USA; and Department of Biology, University of Utah, Salt Lake City, Utah, USA wbaehr@hsc.utah.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D000072661:Ciliopathies / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism
chemical_list: D002148:Calmodulin-Binding Proteins; C498171:IQCB1 protein, human; C000622357:IQCB1 protein, mouse; D006162:Guanylate Cyclase
keywords: Leber congenital amaurosis; Senior-Løken syndrome; nephrocystins; nephronophthisis