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 Chang, Hemant Khanna, Norman Hawes, David Jimeno, Shirley He, Concepcion Lillo, Sunil K. Parapuram, Hong Cheng, Alison Scott, Ron E. Hurd, John A. Sayer, Edgar A. Otto, Massimo Attanasio, John F. O'Toole, Genglin Jin, Chengchao Shou, Friedhelm Hildebrandt, David S. Williams, John R. Heckenlively, Anand Swaroop

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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 ∼15% of patients with retinitis pigmentosa. A truncated CEP290 protein (ΔCEP290) 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.

Original languageEnglish (US)
Pages (from-to)1847-1857
Number of pages11
JournalHuman Molecular Genetics
Volume15
Issue number11
DOIs
StatePublished - Jun 2006

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Retinal Degeneration
Retina
Centrosome
Photoreceptor Connecting Cilium
Proteins
Light Signal Transduction
Vertebrate Photoreceptor Cells
Retinitis Pigmentosa
Cilia
Mutant Proteins
Microtubules
Carrier Proteins
Protein Isoforms

ASJC Scopus subject areas

  • Genetics

Cite this

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. / Chang, Bo; Khanna, Hemant; Hawes, Norman; Jimeno, David; He, Shirley; Lillo, Concepcion; Parapuram, Sunil K.; Cheng, Hong; Scott, Alison; Hurd, Ron E.; Sayer, John A.; Otto, Edgar A.; Attanasio, Massimo; O'Toole, John F.; Jin, Genglin; Shou, Chengchao; Hildebrandt, Friedhelm; Williams, David S.; Heckenlively, John R.; Swaroop, Anand.

In: Human Molecular Genetics, Vol. 15, No. 11, 06.2006, p. 1847-1857.

Research output: Contribution to journalArticle

Chang, B, Khanna, H, Hawes, N, Jimeno, D, He, S, Lillo, C, Parapuram, SK, Cheng, H, Scott, A, Hurd, RE, Sayer, JA, Otto, EA, Attanasio, M, O'Toole, JF, Jin, G, Shou, C, Hildebrandt, F, Williams, DS, Heckenlively, JR & Swaroop, A 2006, '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, vol. 15, no. 11, pp. 1847-1857. https://doi.org/10.1093/hmg/ddl107
Chang, Bo ; Khanna, Hemant ; Hawes, Norman ; Jimeno, David ; He, Shirley ; Lillo, Concepcion ; Parapuram, Sunil K. ; Cheng, Hong ; Scott, Alison ; Hurd, Ron E. ; Sayer, John A. ; Otto, Edgar A. ; Attanasio, Massimo ; O'Toole, John F. ; Jin, Genglin ; Shou, Chengchao ; Hildebrandt, Friedhelm ; Williams, David S. ; Heckenlively, John R. ; Swaroop, Anand. / 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. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 11. pp. 1847-1857.
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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 ∼15{\%} of patients with retinitis pigmentosa. A truncated CEP290 protein (ΔCEP290) 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.",
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AU - Hawes, Norman

AU - Jimeno, David

AU - He, Shirley

AU - Lillo, Concepcion

AU - Parapuram, Sunil K.

AU - Cheng, Hong

AU - Scott, Alison

AU - Hurd, Ron E.

AU - Sayer, John A.

AU - Otto, Edgar A.

AU - Attanasio, Massimo

AU - O'Toole, John F.

AU - Jin, Genglin

AU - Shou, Chengchao

AU - Hildebrandt, Friedhelm

AU - Williams, David S.

AU - Heckenlively, John R.

AU - Swaroop, Anand

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