MUTATIONS IN PEX1 ARE THE MOST COMMON-CAUSE OF PEROXISOME BIOGENESIS DISORDERS

The peroxisome biogenesis disorders (PBDs) are a group of lethal autos omal-recessive diseases caused by defects in peroxisomal matrix protei n import, with the concomitant loss of multiple peroxisomal enzyme act ivities. Ten complementation groups (CGs) have been identified for the PBDs, with CG1 accounting for 51% of all PBD patients. We identified the human orthologue of yeast PEX1, a gene required for peroxisomal ma trix protein import. Expression of human PEX1 restored peroxisomal pro tein import in fibroblasts from 30 CG1 patients, and PEX1 mutations we re detected in multiple CG1 probands. A common PEX1 allele, C843D, is present in approximately half of CG1 patients and has a deleterious ef fect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells rev ealed severe defects in peroxisomal matrix protein import and destabil ization of PEX5, the receptor for the type-1 peroxisomal targetting si gnal, even though peroxisomes were present in these cells and capable of importing peroxisomal membrane proteins. These data demonstrate an important role for PEX1 in peroxisome biogenesis and suggest that muta tions in this gene are the most common cause of the PBDs.