MOLECULAR BIOLOGY OF OUTER RETINA-SPECIFIC PROTEINS

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Retinal pigment epithelium (RPE) cells and photoreceptor cells are functionally and developmentally closely integrated. Derangements of the RPE are involved in certain retinal diseases. However, the RPE is poorly understood at the molecular level. We are characterizing RPE65, a developmentally regulated, conserved 65-kD RPE-specific microsomal membrane-associated protein. We have cloned the cDNA for RPE65 and found that it encodes a novel protein. This protein does not have any predicted transmembrane segments, yet it has a strong affinity for phospholipids, which may be related to its function. The cDNA sequence is being used to overexpress RPE65 protein for functional studies. The potential role of the protein in inducing uveitis also will be studied using recombinant protein. The lack of translation of RPE65 mRNA in cultured RPE cells is being investigated as a possible mechanism of posttranscriptional regulation that may have a bearing on the RPE-retina relationship s well as on RPE transplantation studies. We have isolated a full-length genomic clone for RPE65. It is at least 22 kb in length. We have used the cDNA and genomic sequences to localize the human gene for RPE65 to chromosome 1p31 and the mouse homologue to distal chromosome 3. These do not correspond to any ocular disease gene localized so far. Nonetheless, RPE65 remains a candidate gene for RPE-involved disease.