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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.

Human molecular genetics | Jun 1, 2006

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.

Pubmed ID: 16632484 RIS Download

Mesh terms: Animals | Antigens, Neoplasm | Base Sequence | Carrier Proteins | Centrosome | Disease Models, Animal | Eye Proteins | Gene Deletion | Humans | Mice | Models, Genetic | Molecular Sequence Data | Mutation | Nuclear Proteins | Protein Binding | Retinal Degeneration

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK 1069274
  • Agency: NEI NIH HHS, Id: EY 12598
  • Agency: NIDDK NIH HHS, Id: DK 20572
  • Agency: NEI NIH HHS, Id: R01 EY007042
  • Agency: NEI NIH HHS, Id: P30 EY012598
  • Agency: NCRR NIH HHS, Id: RR 01183
  • Agency: NIDDK NIH HHS, Id: DK 10683-06
  • Agency: NCRR NIH HHS, Id: P40 RR001183
  • Agency: NIDDK NIH HHS, Id: P60 DK020572
  • Agency: NEI NIH HHS, Id: R01 EY007042-20
  • Agency: NEI NIH HHS, Id: R01 EY007758
  • Agency: NEI NIH HHS, Id: R01 EY007961
  • Agency: NEI NIH HHS, Id: EY 07003
  • Agency: NIDDK NIH HHS, Id: P30 DK020572
  • Agency: NEI NIH HHS, Id: EY 13408
  • Agency: NIDDK NIH HHS, Id: DK 064614
  • Agency: NIDDK NIH HHS, Id: R01 DK064614
  • Agency: NEI NIH HHS, Id: EY 07758
  • Agency: NEI NIH HHS, Id: P30 EY007003
  • Agency: NEI NIH HHS, Id: F31 EY007003
  • Agency: NEI NIH HHS, Id: R01 EY013408
  • Agency: NEI NIH HHS, Id: EY 07961

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