HUMAN PEX1 IS MUTATED IN COMPLEMENTATION GROUP-1 OF THE PEROXISOME BIOGENESIS DISORDERS

Human peroxisome biogenesis disorders (PBDs) are a group of geneticall y heterogeneous autosomal-recessive diseases caused by mutations in PE X genes that encode peroxins, proteins required for peroxisome biogene sis, These lethal diseases include Zellweger syndrome (ZS), neonatal a drenoleukodystrophy (NALD) and infantile Refsum's disease (IRD)(1), th ree phenotypes now thought to represent a continuum of clinical featur es that are most severe in ZS, milder in NALD and least severe in IRD2 . At least eleven PBD complementation groups have been identified by s omatic-cell hybridization analysis(2-6) compared to the eighteen PEX c omplementation groups that have been found in yeast, We have cloned th e human PEX1 gene encoding a 147-kD member of the AAA protein family A TPases associated with diverse cellular activities)(7), which is the p utative orthologue of Saccharomyces cerevisiae Pex1p (ScPex1p). Human PEX1 has been identified by computer-based 'homology probing' using th e ScPex1p sequence to screen databases of expressed sequence tags (dbE ST) for human cDNA clones. Expression of PEX1 rescued the cells from t he biogenesis defect in human fibroblasts of complementation group 1 ( CG1), the largest PBD complementation group, We show that PEX1 is muta ted in CG1 patients.