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L. T. Michalovicz, S. Kolandaivelu, V. Ramamurthy; The Leber Congenital Amaurosis (LCA) Protein, AIPL1, is Essential for Cone Photoreceptor cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4144.
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© ARVO (1962-2015); The Authors (2016-present)
LCA4 is a form of severe childhood blindness caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 (Aipl1). An animal knockout model exhibits complete degeneration of both rod and cone photoreceptor cells. The loss of rods in Aipl1-/- mice is linked to defects in rod phosphodiesterase (PDE), an enzyme essential for rod survival and function. However, in Aipl1 knockdown mice, there are no observed cone defects suggesting that AIPL1 is not essential for cone photoreceptor viability. Similar to rd mice, cone death in absence of AIPL1 could be a "bystander" effect of rod cell death. Contradictory to the bystander hypothesis, Aipl1-/- mice have no recordable ERG response at any age tested and show rapid degeneration of cones indicating that AIPL1 is required for cone function and survival. In light of this controversy, our goal was to determine if AIPL1 has a direct effect on cone survival or if cone death in Aipl1-/- mice is the indirect result of rod loss.
We used Nrl-l promoter to drive the expression of hAipl1 transgenically in the Aipl1-/- mouse resulting in hAIPL1 expression exclusively in rods. Rod and cone function was assessed using dark- and light-adapted ERGs, respectively. Protein expression was evaluated by western blot and immunocytochemistry.
Rod morphology and function is restored by transgenic expression of AIPL1, indicating that hAIPL1 can substitute for mAIPL1 despite differences in the protein sequence. However, absence of AIPL1exclusively in cones results in a loss of its function even though cone degeneration is observed at a reduced rate. While protein analysis indicates that rod PDE is recovered by transgenic expression of AIPL1, cone PDE and other cone-specific proteins exhibit a distinct reduction in expression.
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