The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases caused by defects in peroxisome assembly. We have isolated PXR1, a human homologue of the yeast P. pastoris PAS8 (peroxisome assembly) gene. PXR1, like PAS8, encodes a receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Mutations in PXR1 define complementation group 2 of PBDs and expression of PXR1 rescues the PTS1 import defect of fibroblasts from these patients. Based on the observation that PXR1 exists both in the cytosol and in association with peroxisomes, we propose that PXR1 protein recognizes PTS1-containing proteins in the cytosol and directs them to the peroxisome.

Mutations in the PXR1 gene can cause a generalized peroxisome biogenesis disorder (complementation group 2). Fluorescence in situ hybridization with the PXR1 cDNA and two cosmids containing the PXR1 gene was used for the cytogenetic assignment of the gene to chromosome 12p13. Analysis of a radiation hybrid panel for chromosome 12 with a PXR1 gene-based sequence-tagged site (STS) mapped the PXR1 gene between TPI1 and D12S1089. The STS also detects an unusual, highly polymorphic, short tandem repeat (heterozygosity, 0.82). This repeat shows one set of short alleles containing a pentanucleotide repeat and one set of long alleles containing a complex array of different pentanucleotides.