Review of knockout models of Leber congenital amaurosis with impaired genomic control of phototransduction

Genetically modified animal models with knockouts of the phototransduction genes Rpe65, Lrat, Aipl1, Crb1, Crb2, Gucy2e, and Gucy2f (RetGC1 and RetGC2), which are associated with the development of Leber congenital amaurosis (LCA), are being discussed. Knockouts of Rpe65 and Lrat result in a blockade of the retinoid cycle, accompanied by a deficiency of 11-cis-retinal. The Rpe65−/− model is characterized by an accumulation of all-trans-retinyl esters, whereas Lrat−/− demonstrates reduced ester levels due to impaired esterification of all-trans-retinol. The administration of retinoid analogs was found to partially restore rod function and slow their degeneration but did not prevent cone degeneration. Mice with Aipl1 knockout revealed the critical role of the encoded protein in the assembly of phosphodiesterase-6 and the regulation of cyclic guanosine monophosphate (cGMP) levels. Aipl1−/− models demonstrate rapid degeneration of rods and cones beginning shortly after birth. The double knockout of Crb1 and Crb2 leads to the loss of Crumbs complex components, causing severe disruptions in adhesion between photoreceptors and Müller cells. These disruptions result in structural changes in the retina, loss of functional stability, and progressive photoreceptor degeneration. RetGC1−/−/RetGC2−/− models exhibited a significant decrease in cGMP levels, resulting in the closure of ion channels, disruption of membrane potential, photoreceptor apoptosis, and progressive thinning of the outer nuclear layer of the retina. These models emphasize the importance of the studied genes in the pathogenesis of LCA and provide a platform for developing new therapeutic strategies.