Cellular and molecular aspects of Zellweger syndrome and other peroxisome biogenesis disorders.

Peroxisomes are single-membrane-bound organelles present in virtually all eukaryotic cells. They are involved in numerous metabolic processes, both catabolic and anabolic, including beta-oxidation of very long chain fatty acids, metabolism of hydrogen peroxide, plasmalogen biosynthesis and bile acid synthesis. In several genetic diseases, there is either isolated deficiency of a specific peroxisomal protein (single-protein deficiencies) or a defect in the formation of the organelle with loss of multiple peroxisomal functions (peroxisome biogenesis disorders). X-linked adrenoleukodystrophy is an example of the former, and the Zellweger spectrum of the latter. Peroxisome biogenesis disorders are inherited in an autosomal recessive manner and result from mutations in any of at least 12 PEX genes that encode peroxins. This article reviews the peroxisomal system, the clinical, biochemical and molecular aspects of peroxisomal disorders, and discusses recent scientific advances in the understanding of peroxisome biogenesis.

Restoration of PEX2 peroxisome assembly defects by overexpression of PMP70.

The mutant Chinese hamster ovary (CHO) cell line Z78/C has defective peroxisome assembly due to a missense mutation in PEX2, the gene which encodes the 35 kDa peroxisomal integral membrane protein. In humans, PEX2 mutations are responsible for complementation group 10 of the human peroxisome biogenesis disorders (PBD), a genetically heterogeneous group of lethal, autosomal recessive diseases including the Zellweger syndrome and related phenotypes. To develop additional cellular models for Zellweger syndrome, we produced a series of new mutant CHO cell clones in the same complementation group as Z78/C (Z2, Z7, Z22, and Z105). As expected, expression of human PEX2 restores peroxisomal biogenesis in all of these clones. Surprisingly, expression of the human 70 kDa peroxisomal membrane protein (PMP70) also restores peroxisome biogenesis in these same CHO cell clones. We confirmed this effect of PMP70 expression on peroxisome biogenesis by determining the subcellular latency of catalase, the immunohistochemical localization of catalase and the beta-oxidation of very long chain fatty acids (VLCFA). By contrast, expression of a mutant allele of PMP70 identified in a patient with Zellweger syndrome did not restore peroxisome biogenesis in the PEX2-deficient CHO cell clones. Our results indicate that overexpression of PMP70 suppresses the phenotype of PEX2 gene mutations. These observations suggest a functional interaction between PEX2 and PMP70 in the peroxisome membrane.