Predominant Rod Photoreceptor Degeneration in Leber Congenital Amaurosis Associated With AIPL1

Abstract

Abstract: : Purpose: Mutation of AIPL1 caused an unusual retinal vascular morphology in a patient with Leber congenital amaurosis (LCA). The AIPL1 protein is photoreceptor–specific.Whilst the AIPL1 protein is expressed in both cone and rod photoreceptors during development of the human retina, it is restricted to rod photoreceptors in the adult human retina. Therefore, this study was conducted to determine the photoreceptor phenotype and if rod and cone photoreceptors were differentially affected in this LCA patient . Methods: The morphology of the photoreceptors was examined by light– and electron microscopy. Immunohistochemistry and immunofluorescent confocal microscopy was performed using a range of retinal photoreceptor markers. Results: Morphologically, the LCA retina appeared to be cone–dominant with a single layer of cone–like cells remaining in the central retina. Photoreceptor outer segments were absent and the surviving residual inner segments were severely stunted and highly disorganised. Upregulation of glial fibrillary acidic protein (GFAP) was associated with severe degeneration in the LCA retina. No signal was detected for AIPL1 or any of the photoreceptor opsins in the LCA retina, including rhodopsin, L/M – and S – cone opsin. Double labelling with peanut agglutinin (PNA) and wheat germ agglutinin (WGA) supported a cone–dominant phenotype for the surviving photoreceptors in the LCA retina, as did double labelling for cone arrestin, and rod and cone recoverin. The cone arrestin signal was restricted to the residual photoreceptor inner segments and was not detected in the cell bodies, axons or axon terminals of the surviving photoreceptors. Recoverin immunoreactivity was also most intense in the residual photoreceptor inner segments, all of which were double labelled for arrestin and recoverin supporting a cone–dominant derivation for the surviving photoreceptor segments. Conclusions: The phenotype in this patient suggests that although AIPL1 is required for the development of normal rod and cone photoreceptor function, it is only essential for rod and not cone survival in the adult, as the surviving photoreceptors in the LCA patient appeared to be cone–like but were non–functional.

Keywords: retinal degenerations: hereditary • photoreceptors • chaperones