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.
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.
Chang
Bo
B
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Khanna
Hemant
H
Hawes
Norman
N
Jimeno
David
D
He
Shirley
S
Lillo
Concepcion
C
Parapuram
Sunil K
SK
Cheng
Hong
H
Scott
Alison
A
Hurd
Ron E
RE
Sayer
John A
JA
Otto
Edgar A
EA
Attanasio
Massimo
M
O'Toole
John F
JF
Jin
Genglin
G
Shou
Chengchao
C
Hildebrandt
Friedhelm
F
Williams
David S
DS
Heckenlively
John R
JR
Swaroop
Anand
A
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*
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