Phenotype-genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p-Pex6p interaction

The peroxisome bioggenesis disorders (PBDs), including Zellweger syndrome ( ZS), neonatal adrenoleucodystrophy (NALD) and infantile Refsum disease (IRD ), are fatal autosomal recessive diseases caused by impaired peroxisome bio genesis, of which 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, whereas those with NALD a nd IRD show less severity and the mildest features respectively. We have re ported previously that temperature-sensitive peroxisome assembly is respons ible for the mildness of the clinical features of I RD. PEX1 is the causati ve gene for PBDs of complementation group E (CG-E, CGI in the U.S.A. and Eu rope), the PBDs of highest incidence, encoding the peroxin Pex1p of the AAA ATPase family. It has been also reported that Pex1p and Pex6p interact wit h each other. In the present study we investigated phenotype-genotype relat ionships of CGI PBDs. Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37 degreesC, whereas a normal level of Pex1p was detectable at the permissive temperatur e. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634-690, were stably p resent at both temperatures. Pex1p-GS43D interacted with Pex6p at approx. 5 0% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly show ing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stabilit y of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibrob lasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnorma lities, such as those manifested by patients with ZS.