During the last 5 years thirteen separate peroxisomal disorders have been identified and severe mental retardation has been shown to be a consistent feature in ten. All of these disorders can be diagnosed by noninvasive tests and our laboratory has identified more than 2000 patients. This proposal is designed to determine the biochemical and molecular basis of these disorders, to examine the pathogenesis of the mental retardation, and to provide information that will aid the development and evaluation of therapy. This program project application consists of five closely interconnected research projects and three cores. The first three projects study X-lined adrenoleukodystrophy (ALD), the most common peroxisomal disorder. ALD shows striking phenotypic intrafamilial variability and this is examined in Project 1, both to obtain information about natural history, which is required for evaluation of therapy, and to test the hypothesis that the variability is due to the action of a modifier gene. In Project 2, the aims are to isolate and characterize the ALD gene, which has been mapped to Xq28. Project 3 is designed to purify and clone lignoceroyl-CoA ligase, the enzyme that appears to be defective in ALD. The objective of Project 4 will be to characterize the genes the encode peroxisomal proteins and to identify human mutants in an archive of cell lines from patients with peroxisomal disorders assembled in our laboratory. This project will also correlate genotype with the neuropathological alterations that cause mental retardation. In Project 5, the aims are to purify and clone L- pipecolic oxidase, an enzyme that is deficient in all of the disorders of peroxisomes biogenesis. The projects will be supported by molecular biology, biostatistics, and administrative cores.
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