Retinal Degeneration and ABCA4 ABCR

In addition to ABCA1, the ABCA4 (ABCR) gene located on chromosome 1p21 (Tabs 3.1 and 3.2) is another example how several mutations in one ABC transporter gene can cause pleiotropic effects. Thus, many different clinical phenotypes, associated with various forms of eye degeneration, and the age of onset as well as disease severity are associated with distinct mutations in ABCA4 [9]. As summarized in Tab. 3.2, ABCA4 has been found to be a causal gene for a series of retinal diseases. As an effort of several laboratories in 1997 [149-151], mutations in ABCA4 have been identified in Stargadt disease (STGD), a juvenile-onset macular dystrophy characterized by rapid central visual impairment and progressive bilateral atrophy of the retinal pigment epithelium, as well as in the late-onset form termed fundus fla-vimaculatus. Although only 60% of the mutations in the ABCA4 gene of STGD have been determined, all segregated chromosomal regions in these patients have been mapped to a locus between chromosomes 1p13 and 1p22.

In addition to the monogenic STGD, ABCA4 mutations have been described in the autosomal recessive diseases cone-rod dystrophy (CRD) [152, 153] and retinitis pigmentosa (RP) [152, 154-156], which are both genetically and clinically heterogeneous disorders. Cone-rod dystrophy mainly displays cone degeneration, whereas retinitis pigmentosa affects predominantly rod photoreceptors. Age-related macular degeneration (AMD), the leading cause of severe central visual impairment among the elderly, is the fourth disease state associated with ABCA4 dysfunction. The disease is also characterized by progressive accumulation of large quantities of lipofuscin with retinal pigment epithelial cells and delayed dark adaptation [157]. Athough AMD is strongly influenced by environmental factors such as smoking, heterozygous mutations in ABCA4 have been proposed to increase the susceptibility to develop AMD. Thus, the two most frequent AMD-associated ABCA4 variants D2177N and G1961E, increase the risk of developing AMD by approximately 3-fold and 5-fold, respectively [158, 159].

Rod Photoreceptors

Fig. 3.3 Model for the role of ABCA4 (ABCR) in rod outer segments. Left panel: schematic drawing of a rod photoreceptor. Right panel: magnification of rod disc membranes. Rho-dopsin is manufactured from opsin and 11-ci's retinal in the Golgi of the rod inner segment and transported to rod outer segment discs. Upon light absorption the 11-cis form of retinal is converted to an all-trans form, which reacts with phosphatidylethanolamine (PE) to form the Schiff-base product N-retinylidene-PE

(N-RPE). ABCA4 is thought to flip N-RPE to the outer leaflet of the disc membrane. There, all-trans retinal is generated by hydrolsysis of N-RPE and subsequently reduced to all-trans retinol by retinol dehydrogenase prior to its delivery to the retinal pigment epithelial cells and re-esterification [62]. Under the effect of short-wave light or in ABCA4 deficiency, alltrans retinal accumulates, causing photooxida tive damage and generation of toxic A2E (N-retinyl-N-retinylidene ethanolamine) [63].

Fig. 3.3 Model for the role of ABCA4 (ABCR) in rod outer segments. Left panel: schematic drawing of a rod photoreceptor. Right panel: magnification of rod disc membranes. Rho-dopsin is manufactured from opsin and 11-ci's retinal in the Golgi of the rod inner segment and transported to rod outer segment discs. Upon light absorption the 11-cis form of retinal is converted to an all-trans form, which reacts with phosphatidylethanolamine (PE) to form the Schiff-base product N-retinylidene-PE

(N-RPE). ABCA4 is thought to flip N-RPE to the outer leaflet of the disc membrane. There, all-trans retinal is generated by hydrolsysis of N-RPE and subsequently reduced to all-trans retinol by retinol dehydrogenase prior to its delivery to the retinal pigment epithelial cells and re-esterification [62]. Under the effect of short-wave light or in ABCA4 deficiency, alltrans retinal accumulates, causing photooxida tive damage and generation of toxic A2E (N-retinyl-N-retinylidene ethanolamine) [63].

In addition to the above described results based on the phenotypical analysis of ABCA4 mutations, data from in vitro studies and ABCA4 knockout mice have shed light on the transport function of ABCA4 in photoreceptor cells. Recombinant liposome-reconstituted ABCA4 displays all-trans-retinal-stimulated ATPase activity [47, 48, 160] and ABCA4 knockout mice exhibit an acute light-dependent accumulation of all-trans retinal within rod outer segments and a progressive light-dependent culmination of lipofuscin-derived A2E (N-retinyl-N-retinylidene ethanolamine) [161, 162]. Based on these data, a model for the function of ABCA4 in rod disc membranes has been proposed [162]. As summarized in Fig. 3.3, all-trans retinoids, which are released from rhodopsin by photobleaching, react with the primary amine of PE to form the condensation product N-retinylidene-PE (N-RPE). ABCA4 is thought to flip N-RPE to the outer leaflet of the disc membrane, where all-trans retinal is generated by hydrolysis of N-RPE and subsequently re duced to all-trans retinol by retinol dehydrogenase prior to its delivery to the retinal pigment epithelial cells and re-esterification [163].

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