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.

Small organelle, big responsibility: the role of centrosomes in development and disease

“…By contrast, CEP290 mutant mice are viable. Hypomorphic alleles cause retinal degeneration and impaired olfaction [137,138], whereas null animals exhibit a defective cerebellar midline fusion [139]. In humans, BBS4 mutations cause BBS characterized by retinal dystrophy, obesity, cognitive impairments and renal malformation [140].…”

Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

“…21 Another known interaction partner of the RPGRIP1 C-terminal region (RID) is the X-linked RPGR gene, involved in X-linked retinitis pigmentosa type 3. 22 Furthermore, RPGRIP1 has been detected in the retina as a complex with the basal body protein CEP290 30 and in amacrine cells with the neuronal nucleoporin RANBP2. 24 These results suggest that one of the main roles of one or more RPGRIP1 isoforms is to serve as a plastic and dynamic scaffold for proteins or protein modules acting in signaling pathways of different retinal cell subpopulations, thus linking one or more RPGRIP1 isoforms to a set of different clinical phenotypes.…”

Cerebellar development and disease

“…When tested directly, at least three of the encoded proteins, NPHP1, CEP290 and RPGRIP1L have demonstrated localization to the basal body or cilium [32,[35][36][37], further suggesting a role at the cilium or basal body. Remarkably, CEP290 was concurrently identified as mutated in the rd16 mouse [38] and rdAc cat [39] both models of retinal dystrophy. In these models there is failure to transport rhodopsin to the photoreceptor outer segment and of disk morphogenesis.…”