Identification of novel PEX gene and functional analysis of Pexlp in peroxisome biogenesis

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1) We investigated phenotype-genotype relationships of CGI peroxisome biogenesis disorders (PBDs). Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37℃, whereas a normal level of Pexlp was detectable at the permissive temperature. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634-690, were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at appox. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stability of Pexlp reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS.2) We showed that PEX6, the CG4 pathogenic gene, restored peroxisome assembly in CG6 PBD fibroblasts. This patient was compound heterozygous for PEX6 alleles. Accordingly, human PBDs are classified into 12 CGs by merging CG6 with CG4.3) We recently isolated human PEX26 encoding a novel, 34-kDa type II peroxisomal membrane protein, using a CHO cell mutant ZP167. PEX26 expression restored peroxisomal protein import in only the CG8 PBD patient's fibroblasts. This patient possessed a homozygous, inactivating pathogenic point mutation, R98W. Accordingly, we can state that all of pathogenic genes responsible for 12 CGs PBDs have been cloned. Moreover, Pex6p and Pex1p of the AAA ATPase family were co-immunoprecipitated with Pex26p. Together with several lines of morphological evidence, we concluded that Pex26p recruits Pex6p-Pex1p complexes to peroxisomes.