Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients

To investigate mechanisms related to functions of the peroxisome targeting signal (PTS) 1 receptor, Pex5p, we analyzed peroxisome matrix protein impor t in fibroblasts from three patients with peroxisome biogenesis disorders, all with different mutations in the PEX5 gene. The patients 2-01 (Zellweger syndrome) and 2-05 (neonatal adrenoleukodystrophy) have the reported mutat ions, R390X and N489K, and patient 2-03 (infantile Refsum disease) has a ne wly identified mutation, S563W. Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports despite the PEX5 defect, findings in contras t with fibroblasts from 2-05 (N489K) severely defective in PTS1 import and those from 2-01 (R390X) severely defective in both PTS1 and PTS2. The PTS1 receptor in 2-03 is functional for only the C-terminal -SKL sequence (acyl- CoA oxidase) and had little or no function for C-terminal -AKL (D-bifunctio nal protein and sterol carrier protein 2) and -KANL (catalase) sequences, r espectively. After transfection of these mutated PEX5 cDNA into the PEX5-de fective CHO mutant, transformants of ZP102 revealed that each mutation was responsible for each dysfunction of the PTS1 import. It seems apparent that -AKL and -KANL are poorer variants of PTS1 and are likely to be more susce ptible to effects of mutation of its receptor, Pex5p. (C) 1999 Academic Pre ss.