Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum~s disease, hyperpipecolic acidemia, and classical rhizomelic chondrodysplasia punctata are a genetically heterogenous group of lethal inherited diseases collectively referred to as the peroxisome biogenesis disorders (PBD). These diseases occur at a frequency of approximately 1/50,000 live births, can manifest a wide range of phenotypes, and are caused by mutations in any of at least 10 different genes. The only common phenotypes of PBD patients are that they suffer from e=severe mental retardation and exhibit a defect in import of at least one class of peroxisomal protein. Using a yeast genetic system, we and others have identified a number of peroxisome assembly protein (PAS) genes required for normal import of peroxisomal matrix proteins. We recently identified the human gene PXR1 on the basis of its similarity to the yeast Pichia pastoris PAS8 gene. The fact that mutations in PXR1 are responsible for complementation group 2 of the PBD provided the first demonstration that human orthologs of yeast PAS genes are defective in the PBD and proved that yeast PAS sequences can be used to clone human PBD genes. The goal of this project is to identify additional human PBD genes by extension of this homology probing strategy. We propose to expand our current molecular analysis of peroxisome assembly in Pichia pastoris in order to identify all genes involved in proxisomal protein import and peroxisome assembly in this yeast. We will study these new yeast PAS genes, proteins and mutants to gain a better understanding of the peroxisome assembly process and use the sequence of these new PAS genes to determine the role of two candidate human PBD genes (PXAAA1 and PXSH3) in peroxisome assembly and human disease.
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