At least 50% of new cases of legal blindness in the pediatric age group of the United States can be attributed to genetic causes but our understanding of the genetic basis of ocular disease is still very limited. Furthermore, clinical heterogeneity occurs in disease which appear to be the same and/or carry the same name but are caused by more than one genetic abnormality. Thus, it will be necessary to evaluate a large number of families to identify putative genes. The normal function of genes which cause isolated ocular diseases or have significant ocular manifestations such as autosomal dominant congenital cataracts and retinal degenerations is unknown. The major focus of this research proposal is to use recombinant DNA techniques to map and identify genes causing genetic eye diseases. We plan to confirm or exclude cosegregation between the RFLPs identified by eye-specific probes and the genes for various inherited eye diseases; we specifically plan to study autosomal dominant congenital cataracts and retinal degenerations. If cosegregation is excluded, standard linkage analysis will be performed. In the case of an eye disease for which a chromosomal assignment has been tentatively made by prior linkage analysis, probes in close proximity to the gene encoding the disease, especially candidate gene probes will be used to identify RFLPs. We also plan to map all available eye-specific DNA probes using somatic cell hybridization, and in situ hybridization. Information gathered by the proposed studies will improve our understanding of the genes involved in the various disorders, their normal functions, and how these functions are altered by mutations. Such information will improve disease classification and will identify genetic heterogeneity among disorders of apparently similar phenotype. The accuracy of genetic counseling will be enhanced. Furthermore, understanding the function of the mutated genes may provide insight into the pathogenesis of the disorders and provide clues to delay and/or prevent the expression of the mutated gene. This becomes particularly important if there are multiple genetic loci causing the same or similar phenotypic features. The means to manage and alter the expression of different mutant genes probably would be different and specific for each locus.
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