The oculocerebrorenal syndrome of Low (OCRL) is an X-linked inborn error of metabolism of unknown etiology. Affected males are retarded and have congenital cataracts and renal tubular dysfunction. The locus for OCRL has been mapped to the Xq25 region by linkage to restriction fragment length polymorphisms (RFLPs) in Xq24-26 and by the occurrence of OCRL in a female with an X/3 translocation with breakpoint at Xq25. A yeast artificial chromosome (YAC) containing a 100-120 kb human insert was isolated in another, collaborating laboratory and made available to this laboratory. This YAC, RS88, appears to contain sequences from either side of the breakpoint in the X;3 translocation in the female with OCRL. Using sequences from within RS88, overlapping genomic sequences in lambda or cosmid vectors will be isolated until the entire region around 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 lens, kidney, m brain and fibroblasts, (all target tissues for OCRL), (iii) demonstration of mutation, deletional or otherwise, of these putative exonic sequences in OCRL 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 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. The long-term objective is to identify the gene for a human mental retardation syndrome through its location rather than its function and then to characterize the gene and in 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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