Choroideremia (McKusick #30310) is an X-linked retinal dystrophy of unknown pathogenesis that causes progressive vision loss and atrophy of the photoreceptors and retinal pigmented epithelium (RPE) in hemizygous males. The disease locus maps to xq21.2 based on linkage analysis in families and on chromosome deletion and translocation in affected patients. A female with choroideremia has a balanced translocation between Xq and 13p that apparently interrupts the choroideremia gene and causes disease through inactivation of the normal X. An anonymous probe, pH165.1, isolated in this laboratory maps proximal to and <50 kilobases from the translocation breakpoint in this female. Overlapping genomic sequences in lambda or cosmid vectors will be isolated until the entire region between pH165.1 and the breakpoint, and sequences distal to the breakpoint have been cloned. All DNA from this region will be tested for whether it contains exons of a candidate gene based on (i) conservation of nucleic acid homology between man and other mammals, (ii) expression of the sequence in retina and RPE, (iii) demonstration of mutation, deletional or otherwise, of these putative exonic sequences in choroideremia probands. When a candidate gene is identified, (1) its entire mRNA sequence and genomic structure will be characterized. (2) the mutations responsible for the disease will be determining by sequencing the exons and intron-exon boundaries of the gene in the DNA of patients (3) antibodies to the gene product will be raised and used to determine the tissue(s) in the retina in which the gene is expressed and the cellular and subcellular localization of the gene product. (4) the promoter and enhancer sequences responsible for control of gene expression will be identified. (5) the homologous murine gene will be isolated to use for assessing the developmental timing of expression in mouse embryos as well as for beginning studies to develop a mouse model through homologous recombination of mutant gene sequences in the embryonal stem cell system. The long-term objective is to identify the gene for a human eye disease through its location rather than its function and then to characterize the gene and its expression as well as the mutations responsible for the disease in man. The ultimate goal is to understand what the gene product is and how defects in the gene produce disease.
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