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What can we learn about AMD from other retinal diseases ?
| Content Provider | Semantic Scholar |
|---|---|
| Author | Zack, Donald J. Dean, Michael Molday, Robert S. Nathans, Jeremy Redmond, T. Michael Edwin, Milgrom Stone Swaroop, Anand Valle, David Weber, Bernhard H. F. |
| Copyright Year | 1999 |
| Abstract | Correspondence to: Donald J. Zack, Johns Hopkins University School of Medicine, 809 Maumenee, 600 North Wolfe Street, Baltimore, MD, 21287; Phone: (410) 502-5230; FAX: (410) 502-5382; email: dzack@bs.jhmi.edu Age-related macula degeneration (AMD) can be thought of as a sub-type of retinal degeneration. Although the primary site of injury in AMD is unknown, it is ultimately the loss of photoreceptor function that leads to visual loss. As described in the accompanying article [1], one approach to gaining a better understanding of the disease process is to directly study the genetics of AMD. A second and complementary approach is to take advantage of the increasing body of knowledge about the genetics and molecular basis of other forms of photoreceptor degeneration (see RetNet). Although the specific genes involved, in many cases, may turn out to be different, knowledge about the genetics and biology of photoreceptor cell death in general is likely to provide insights that will be helpful in understanding the pathogenesis of AMD. This latter approach was the unifying theme of the session entitled “What can we learn about AMD from other retinal diseases?” As noted in the accompanying article [1], some of the difficulties in studying AMD are its late onset (which limits the availability of large pedigrees), complex genetics, and probable strong environmental component. In such situations, it can be useful to study related clinical diseases that demonstrate earlier clinical presentation and simpler Mendelian inheritance patterns. As one example of the successful use of this approach, analysis of a rare juvenile form of glaucoma led to the identification and cloning of a gene that, at least in some populations, is responsible for 2-4% of the far more common adult onset primary open angle glaucoma [2]. Based on a similar rationale, a number of groups have been studying early onset forms of macular degeneration that show Mendelian inheritance patterns, such as Stargardt disease and Best disease. Several talks in the session were devoted to ABCR/RIM, the gene that is responsible for most, and perhaps all, cases of Stargardt disease. Jeremy Nathans reviewed the positional cloning of the ABCR/RIM [3]. He also pointed out that ABCR/RIM was independently cloned using a protein purification and sequencing approach [4]. ABCR/RIM encodes a 220 kd retina-specific member of the ABC transporter superfamily, which includes such proteins as CFTR, P-glycoprotein and TAP1 and TAP2. Immunocytochemical studies have demonstrated that it is localized to disc membranes within rod outer segments [5]. This finding of rod-specific expression was somewhat surprising in that, based on the clinical characteristics of Stargardt disease, many investigators suspected that the primary gene product would be expressed in RPE cells and/or perhaps cones. Furthermore, the absence of ABCR/RIM in cones suggests either that cones express a different transporter that functions analogously, or that the continuity between cone outer segment discs and the plasma membrane facilitates transport so that an ABCR/RIM homologue is not required. A major unresolved question is what is the function of ABCR/RIM; more specifically, what does it transport? If, like rhodopsin, some fraction of the ABCR/RIM protein resides in the rod outer segment plasma membrane, then ABCR/RIM may transport a small molecule or ion into or out of the outer segment. An alternative and intriguing possibility is that ABCR/RIM facilitates the movement of a small molecule within the rod outer segment, specifically between the luminal and cytosolic faces of the disc membrane. Such a function could be analogous to the lipid “flippase” activity seen in the mdr class of ABC transporters. In this regard, it is interesting that a major constituent of human RPE lipofuscin, which is associated with normal aging, has been identified as N-retinyl© Molecular Vision |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://epub.uni-regensburg.de/35305/1/v5a30-zack.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
