Defective PEX gene products correlate with the protein import, biochemicalabnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders

Peroxisome biogenesis disorders (PBD) comprise three phenotypes including Z ellweger syndrome (ZS) (the most severe), neonatal adrenoleucodystrophy; an d infantile Refsum disease (IRD) (the most mild), and can be classified int o at least 12 genetic complementation groups, which are not predictive of t he phenotypes. Several pathogenic genes for PBD groups have been identified , but the relationship between the defective gene products and phenotypic h eterogeneity has remained unclear. We identified a mutation in the PEX2 gen e in an IRD patient with compound heterozygosity for a missense mutation an d the known nonsense mutation detected in ZS patients. In transfection expe riments using the peroxisome deficient CHO mutant, Z65 with a nonsense muta tion in the PEX2 gene, we noted the E55K mutation had mosaic activities of peroxisomal protein import machinery and residual activities of peroxisomal functions, including dihydroxyacetone phosphate acyltransferase and beta o xidation of very long chain fatty acids. The nonsense mutation severely aff ects these peroxisomal functions as well as the protein import. These data suggest that allelic heterogeneity of the PEX gene affects the peroxisomal protein import and functions and regulates the clinical severity in PBD.