More than 145 well documented diseases and syndromes exhibit X-linked inheritance. Among these are a number of disorders which predominantly affect the central nervous system, many associated with mental retardation; 7 immunological disorders; 12 syndromes with predominant skeletal, connective tissue or cutaneous manifestations; 4 types of X- linked deafness and 27 X-linked eye disorders. The genes underlying only a fraction of these diseases have been identified. Two areas of the X- chromosome short arm encode genes for multiple eye disorders: proximal Xp21-p11.2 and Xp22.2-p22.1. We propose to study two subregions of proximal Xp21-p11.2 that specify genes involved in X-linked retinitis pigmentosa. A recently identified conserved sequence region near the breakpoint of an Xp21 deletion in the male BB with a contiguous gene syndrome that included retinitis pigmentosa will be evaluated as a candidate for the RP3 gene. The distance separating the proximal breakpoint of the BB deletion from that of another male, SB, with chronic granulomatous disease, the McLeod phenotype and retinitis pigmentosa will be determined and the entire RP3 target region searched for transcription units as well as rearrangements indicative of the gene. For the RP2 region, we propose to develop a dense bank of conserved sequence DNA probes from a small insert library of flow sorted X-chromosomes and to utilize these probes, together with reference markers, to complete a large fragment, long range restriction map of the region between DXS426 and DXS7. This map, together with that for the DXS255-DXS426 interval, will provide a framework for a systematic search for the RP2 gene. In other studies, we will characterize a gene with predominant expression in fetal brain that is derived from a region of chromosome 11p implicated in mental retardation.
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