Biological characterization of gene response in Rpe65‐/‐ mouse model of Leber's congenital amaurosis during progression of the disease

RPE65 is the retinal isomerase essential for conversion of all‐trans‐retinyl ester to 11‐cis‐retinolin the visual cycle. Leber's congenital amaurosis (LCA),an autosomal recessive form of RP resulting in blindness, is commonly caused by mutations in the Rpe65gene. Whereas the molecular mechanisms by which these mutations contribute to retinal disease remain largely unresolved, affected patients show marked RPE damage and photoreceptor degeneration. 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 altered expression of genes involved in phototransduction, apoptosis regulation, cytoskeleton organization, and extracellular matrix (ECM) constituents. Cone‐specific phototransduction genes arestrongly decreased, reflecting early loss of cones. In addition, remaining rods show modified expression of genes encoding components of the cytoskeleton and ECM. This may affect rod physiology and interaction with the adjacent RPE and lead to loss of survival signals, as reflected by the alteration of apoptosisrelated genes 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 toward retinal cell death.—Cottet, S., Michaut, L., Boisset, G., Schlecht, U., Gehring, W., Schorderet, D. F. Biological characterization of gene response in Rpe65‐/‐ mouse model of Leber's congenital amaurosis during progression of the disease. FASEB J. 20,2036–2049 (2006)