The goal of this study is the molecular and phenotype study of individuals with peroxisomal disorders. Molecular genetic techniques will be used to identify genes responsible for inborn errors of peroxisome biogenesis and function in order to understand the pathogenesis of the phenotype as it relates to mental retardation. An archive of lymphoblastoid and transformed fibroblast cell lines, from well characterized patients including the entire range of peroxisomal disorders, will be assembled. Human cDNA and genomic clones of the major peroxisome integral membrane proteins (PMP70 and PMP22) and three matrix enzymes (3-oxoacyl-CoA thiolase, bifunctional enzyme and acyl-CoA oxidase) will be analyzed and assigned to chromosomal loci. Their genomic organization and sequence will be examined for molecular hallmarks which could account for the coordinate expression of peroxisomal genes and provide a means for identifying additional putative peroxisomal genes. The signal that targets PMPs to the peroxisome membrane will be determined using in vivo and in vitro expression and transport systems. A search for mutations will be made among the archive of cell lines using Northern analysis, strand gel electrophoresis and sequencing. Candidate mutations for peroxisomal disorders will be evaluated by analysis of gene expression and linkage studies in family members. Correlations between genotype and phenotype will focus on mental retardation, such as defects in neuronal migration, using in-vivo magnetic resonance imaging and post-mortem neuropathologic examination. These studies should improve the understanding of peroxisome biogenesis, pathophysiology, and provide insights about mechanisms controlling neuronal migration.
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