IDENTIFICATION OF PEX10, THE GENE DEFECTIVE IN COMPLEMENTATION GROUP-7 OF THE PEROXISOME-BIOGENESIS DISORDERS

The peroxisome-biogenesis disorders (PBDs) are a group of genetically heterogeneous, lethal diseases that are characterized by neuronal, hep atic, and renal abnormalities; severe mental retardation; and, in thei r most severe form, death within the 1st year of life. Cells from all PBD patients exhibit decreased import of one or more classes of peroxi some matrix proteins, a phenotype shared by yeast per mutants. We iden tified the human orthologue of yeast PEX10 and observed that its expre ssion rescues peroxisomal matrix-protein import in PBD patients' fibro blasts from complementation group 7 (CG7). In addition, we detected mu tations on both copies of PEX10 in two unrelated CG7 patients. A Zellw eger syndrome patient, PBD100, was homozygous for a splice donor-site mutation that results in exon skipping and loss of 407 bp from the PEX 10 open reading frame. A more mildly affected neonatal adrenoleukodyst rophy patient was a compound heterozygote for a missense mutation in t he PEX10 zinc-binding domain, H290Q, and for a nonsense mutation, R125 ter. Although all three mutations attenuate PEX10 activity, the two al leles detected in the mildly affected patient, PBD052, encode partiall y functional PEX10 proteins. PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal membrane proteins but do not impor t peroxisomal matrix proteins, indicating that loss of PEX10 has its m ost pronounced effect on peroxisomal matrix-protein import.