XLPRA, an X-linked retinal degeneration, is the canine equivalent of human RP3. RP3 maps to a 520 kb interval between OTC and DXS1110. RPGR is the only gene for which RP3-causal mutations are known, yet most RP3 patients do not appear to have RPGR mutations. RPGR mutations yet to be identified might account for the balance of RP3 patients. If not, then other genes located in this interval must be responsible. Two distinct models of XLPRA, XLPRA1 and XLPRA2, cosegregate with RPGR and, in both, the RPGR cDNA sequence is normal. Our objective is to use XLPRA dogs to determine 1) do RPGR mutations cause the disease(s), or 2) can novel disease genes in this region be incriminated for either retinal degeneration phenotype? Identification of the gene(s) and mutation(s) responsible for XLPRA will allow for studies of the molecular mechanisms of these diseases, and provide new large animal models for pre-clinical studies and therapy. We will first refine the XLPRA1 and XLPRA2 minimal regions by linkage, recombination and physical mapping. If these regions overlap, we will also define their minimum common zero- recombination interval under the hypothesis that XLPRA1 and XLPRA2 represent diseases caused by different mutations in the same gene. Under this hypothesis, the combined pedigrees yields much greater power to reduce the search area to significantly less than 1 Mb. If RPGR falls within the zero recombination region for either or both diseases, we will examine RPGR genomic sequence in detail for deletions or rearrangements in the appropriate disease(s). In the absence of such RPGR genomic alterations, full genomic sequencing of wild type canine RPGR will be done from RPGR-specific canine BACs, followed by genomic sequencing of the gene for both XLPRA1 and XLPRA2. If RPGR is excluded by these analyses for either disease, we will make a minimal tiling path of canine BACs and cosmids from the XLPRA zero-recombination interval, and evaluate other genes, ESTs and conserved sequences identified therein.
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