The main goal of this laboratory is to isolate and characterize genes involved in ocular disease processes. Our current focus is on the identification of genes that are specific to the macular region of the retina/PE/choroid complex. We hope this will lead to the isolation of candidate genes for macular degenerations. We have taken two general approaches to isolate these genes. The first is a subtractive cDNA cloning approach that uses our own solid-phase subtraction technique (BBRC, 1995), subtracting macular from peripheral retina samples. Using this approach, we have already cloned, identified, and chromosomally mapped a number of genes that are either enriched in or specific to the macular region of the neural retina (BBRC, 1995). One of these is under investigation as a candidate for Best's macular dystrophy in 11q13. We are also using the same approach to isolate and identify genes in the macular region of the PE/choroid. This subtraction has yielded significantly fewer genes. Nevertheless, some of these are indeed enriched in the macular PE/choroid over the peripheral region. We are hopeful that this approach will yield new genes that can be used as candidates for retinal degenerations as well as to better define normal retinal pigment epithelium function in the macular region. The second approach is cloning and studying selected genes that are of importance to retinal function. An example of this is our work on the human hydroxyindole-O-methyltransferase gene (HIOMT), which contains a retina-specific promoter and a separate pineal promoter. This work has also been expanded to the cloning and characterization of the human serotonin N-acetyltransferase gene (Genomics, 1996). These genes code for the expression of the enzymes catalyzing the last two steps of melatonin biosynthesis and are almost exclusively expressed in the pineal gland and retina. Although the genomic location of these two genes rules them out as candidates for any of the known retinal degenerations, they may play a role in the more complex polygenic retinal disorders such as the age-related macular degenerations. In the future, we would like to expand our work to perform large-scale screening of patients by using our candidate genes. We are currently analyzing patients with Best's macular dystrophy at 11q13.1 for mutations in RPB7 and autosomal dominant retinitis pigmentosa at 17p13.3 (RP13) for mutations in PEDF.
