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S. Cottet, L. Michaut, G. Boisset, Y. Arsenijevic, U. Schlecht, F.L. Munier, W. Gehring, D.F. Schorderet; Biological Characterization of Gene Response in Rpe65–/– Mouse Model of Leber's Congenital Amaurosis During Progression of the Disease . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4560.
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Retinitis pigmentosa (RP) is a group of inherited conditions leading to progressive loss of vision accompanied by photoreceptor cell death. RPE65, abundantly expressed in the retinal pigment epithelium (RPE), is the retinal isomerase essential for the conversion of all–trans–retinyl ester to 11–cis–retinol in the visual cycle. Leber's congenital amaurosis (LCA), an autosomal recessive form of RP resulting in blindness, is commonly caused by mutations in the Rpe65 gene. Whereas the molecular mechanisms by which these mutations contribute to retinal disease remain largely unresolved, affected patients show marked RPE damage and photoreceptor degeneration.
To identify the signaling pathways at the initiation of the degenerative process, we evaluated gene expression in Rpe65–/– mouse model of LCA before and at the onset of photoreceptor cell death in 2, 4 and 6 month–old animals.
Microarray analysis demonstrates significant altered expression of genes involved in diverse cellular pathways including phototransduction, apoptosis regulation, cytoskeleton organization and extracellular matrix (ECM). We observe in this model that cone–specific phototransduction genes are strongly decreased, reflecting early loss of cones. In addition, remaining rods show modified expression of genes encoding components of the cytoskeleton and ECM. This may impact on rod physiology and interaction with the adjacent RPE and lead to loss of survival signals as reflected by the inhibition of genes with anti–apoptotic functions.
Together, these results suggest that RPE65 defect triggers an overall remodeling of the neurosensitive retina that may, in turn, disrupt photoreceptor homeostasis and induce apoptosis signaling cascade towards retinal cell death.
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