X-LINKED RETINITIS PIGMENTOSA (RP3): SCREENING FOR NEW MUTATIONS AND PROMOTER ANALYSIS OF RPGR GENE

X-linked retinitis pigmentosa (XLRP) is a severe form of progressive retinal degeneration, which affects about 1 in 25000 of the population. The gene for the most common form of XLRP, RP3, has been localised in Xp21.1 by linkage analysis. However, genetic heterogeneity suggests the presence on X chromosome of other loci. Our group has been involved in a collaborative effort, which has identified and isolated the RPGR gene. Its N-terminal half shows homology to RCC1, a guanine nucleotide exchange factor for the small nuclear GTPase Ran. Mutations in the RPGR gene are the only cause of RP3 and account for the disease in over 70% of XLRP patients. The RPGR gene shows a complex pattern of alternative splicing, although disease-causing mutations are confined to a single low abundance transcript (RPGR-ORF15), consisting of the RCC1-like domain and a novel acidic domain of unknown function. The regulators of RPGR expression are unknown but our data indicate that these are binding sites for two retina specific transcriptional factors, CRX and Brn-3b. These are specific transcription factors that control and maintain the terminal differentiation of the photoreceptors and a subtype of ganglion cells, respectively. We will perform: biochemical and functional studies of the novel RPGR-ORF15, characterise regulatory regions in the promoter, and isolate new genes involved in XLRP or other form of retinal disorders. We believe that this project will give us the important tools to study the role of RPGR in the physiology of the retina. The analysis of the transcriptional elements of the promoter will add data on the control of RPGR expression for expansion of new researches on the cell-tissue transcriptional network in retinal cells. Analysing new XLRP genes is an important step towards a better understanding of the genetic heterogeneity of the RP.