title: In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse.
abstract: Centrosome- and cilia-associated proteins play crucial roles in establishing polarity and regulating intracellular transport in post-mitotic cells. Using genetic mapping and positional candidate strategy, we have identified an in-frame deletion in a novel centrosomal protein CEP290 (also called NPHP6), leading to early-onset retinal degeneration in a newly identified mouse mutant, rd16. We demonstrate that CEP290 localizes primarily to centrosomes of dividing cells and to the connecting cilium of retinal photoreceptors. We show that, in the retina, CEP290 associates with several microtubule-based transport proteins including RPGR, which is mutated in approximately 15% of patients with retinitis pigmentosa. A truncated CEP290 protein (DeltaCEP290) is detected in the rd16 retina, but in considerably reduced amounts; however, the mutant protein exhibits stronger association with specific RPGR isoform(s). Immunogold labeling studies demonstrate the redistribution of RPGR and of phototransduction proteins in the photoreceptors of rd16 retina. Our findings suggest a critical function for CEP290 in ciliary transport and provide insights into the mechanism of early-onset photoreceptor degeneration.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.forename: Norman
authors.initials: N
authors.lastname: Hawes
authors.forename: David
authors.initials: D
authors.lastname: Jimeno
authors.forename: Shirley
authors.initials: S
authors.lastname: He
authors.forename: Concepcion
authors.initials: C
authors.lastname: Lillo
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Parapuram
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Alison
authors.initials: A
authors.lastname: Scott
authors.forename: Ron E
authors.initials: RE
authors.lastname: Hurd
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Chengchao
authors.initials: C
authors.lastname: Shou
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure*; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D011485:Protein Binding; D012162:Retinal Degeneration / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C513600:Cep290 protein, mouse; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D009687:Nuclear Proteins; C513598:RPGR protein, mouse