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Human Molecular Genetics Advance Access originally published online on April 21, 2006
Human Molecular Genetics 2006 15(11):1847-1857; doi:10.1093/hmg/ddl107
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

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

Bo Chang1,{dagger}, Hemant Khanna2,{dagger}, Norman Hawes1, David Jimeno5,6, Shirley He2, Concepcion Lillo5,6, Sunil K. Parapuram2, Hong Cheng2, Alison Scott2, Ron E. Hurd1, John A. Sayer3, Edgar A. Otto3, Massimo Attanasio3, John F. O'Toole3, Genglin Jin7, Chengchao Shou7, Friedhelm Hildebrandt3,4, David S. Williams5,6, John R. Heckenlively2 and Anand Swaroop2,4,*

1The Jackson Laboratory, Bar Harbor, ME 04609, USA, 2Department of Ophthalmology and Visual Sciences, 3Department of Pediatrics and 4Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA, 5Department of Pharmacology and 6Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0912, USA and 7Department of Biochemistry and Molecular Biology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing 100034, China

* To whom correspondence should be addressed at: W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA. Tel: +1 7347633731; Fax: +1 7346470228; Email: swaroop{at}umich.edu

Received March 7, 2006; Accepted April 13, 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 ~15% of patients with retinitis pigmentosa. A truncated CEP290 protein ({Delta}CEP290) 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} The mouse Cep290 cDNA and gene sequence correspond to GenBank accession no. XM_618806.


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