Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders

The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (Z S), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) , are autosomal recessive diseases caused by deficiency of peroxisome assem bly as well as malfunction of peroxisomes, where >10 genotypes have been re ported. ZS patients manifest the most severe clinical and biochemical abnor malities, while those with NALD and IRD show the least severity and the mil dest features, respectively. PEX1 is the causative gene for PBDs of complem entation group I (CG1), the highest incidence PBD, and encodes the peroxin, Pex1p, a member of the AAA ATPase family. In the present work, we found th at peroxisomes were morphologically and biochemically formed at 30 but not 37 degrees C, in the fibroblasts from all CG1 IRD patients examined, wherea s almost no peroxisomes were seen in ZS and NALD cells, even at 30 degrees C. A point missense mutation, G843D, was identified in the PEX1 allele of m ost CG1 IRD patients. The mutant PEX1, termed HsPEX1G843D, gave rise to the same temperature-sensitive phenotype on CG1 CHO cell mutants upon transfec tion. Collectively, these results demonstrate temperature-sensitive peroxis ome assembly to be responsible for the mildness of the clinical features of PEX1-defective IRD of CG1.