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Cristy A. Ku, Visvanathan Ramamurthy; A Novel Animal Model Of RP And Cone-rod Dystrophy Associated With Aipl1 Hinge Mutation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1624.
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© ARVO (1962-2015); The Authors (2016-present)
Defects in Aipl1 (aryl hydrocarbon receptor interacting protein like-1) are associated with autosomal recessive Leber congenital amaurosis (LCA), a severe and rapid degeneration mimicked in the Aipl1 null mouse. Interestingly, Aipl1 defects are also linked to autosomal dominant juvenile retinitis pigmentosa and cone-rod dystrophy. One such mutation is P351Δ12, a 12-bp deletion in the primate specific C-terminal hinge region. The main goal of this work is to understand the mechanism behind Aipl1 defects leading to dominant disease and the importance of the hinge region in function and survival of photoreceptor cells.
Transgenic mice were generated expressing either N-terminal Flag tagged wildtype human AIPL1 (hAIPL1) or P351Δ12 hAIPL1, under the control of a 2.3 kb mouse Crx promoter, active beginning at E12.5 in both rod and cone photoreceptors (Furukawa et al., 2002). Transgenic positive founders were backcrossed with Aipl1 null mice. Transgene expression was examined by immunoblotting with Flag and hAIPL1 antibodies. Photoreceptor function and survival was assessed by electroretinography (ERG) and immunocytochemistry.
Both mutant P351Δ12 hAIPL1 and wildtype hAIPL1 expressed at similar levels. However, ERG responses of P351Δ12 hAIPL1 in an Aipl1-/- background showed an early (P18) dramatic reduction in photopic responses and 50% decline in scotopic responses. In contrast, wildtype hAIPL1 fully rescued rod and cone vision in Aipl1-/- mice into late adulthood. Further biochemical and morphological analyses are being conducted to examine the cause of ERG dysfunction.
This novel model of retinal degeneration associated with Aipl1 P351Δ12 mutation, shows visual deficits and degeneration that is less drastic than Aipl1 null mice. This indicates the greater treatment potential in patients with mutations in this region as compared to the common nonsense W278X Aipl1 mutation. Mutant mice showed a greater detriment to cone photoreceptors, in agreement with cone-rod dystrophy associated with this mutation. The deficits observed in P351Δ12 hAIPL1 mice demonstrate the importance of the primate specific region in proper functioning of AIPL1 in photoreceptor cells.
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