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Balajikarthick Subramanian, Manisha Anand, Hemant Khanna; Ablation Of Raf-1 Kinase Inhibitory Protein (RKIP) Improves Photoreceptor Structure and Function in a Cep290-Mutant Mouse Model Of Severe Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6317.
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Mutations in the CEP290 gene are a frequent cause of childhood blindness disorder, Leber congenital amaurosis (LCA). Not much is known about the mode of action of CEP290 in the retina. We previously showed that CEP290 interacts with RKIP and that RKIP protein is abnormally accumulated in rd16 (retinal degeneration 16) mouse, a model of Cep290- associated retinal degeneration. The purpose of this study is to evaluate the role of RKIP accumulation in mediating photoreceptor degeneration in the rd16 mouse.
rd16/rd16:Rkip-/- double homozygous knock out mice were generated by breeding rd16/rd16 and Rkip-/- mice (both on C57BL6/J background). Photoreceptor structure and function were evaluated by Histology, Transmission electron microscopy (TEM), Immunofluorescence microscopy and Electroretinography (ERG).
We detected improved photoreceptor structure in the double homozygous mutant mice compared to rd16 at postnatal day 18 (P18). In addition, Rhodopsin and M-opsin staining in rd16/rd16:Rkip-/- mice showed increased outer segment localization compared to rd16/rd16 or rd16/rd16:Rkip+/-. Moreover, ERG analysis showed ~40% recovery of scotopic A-wave response in rd16/rd16:Rkip-/- mice as compared to rd16/rd16.
We propose that accumulation of RKIP due to mutation in CEP290 is a critical step in the pathogenesis of associated severe retinal degeneration. Altering RKIP levels may potentially be used in combination with other modalities as an approach to treat such disorders.
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