Disorders of Peroxisome Biogenesis Due to Mutations in PEX1: Phenotypes and PEX1 Protein Levels

Abstract

Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are clinically overlapping syndromes, collectively called "peroxisome biogenesis disorders" (PBDs), with clinical features being most severe in ZS and least pronounced in IRD. Inheritance of these disorders is autosomal recessive. The peroxisome biogenesis disorders are genetically heterogeneous, having at least 12 different complementation groups (CGs). The gene affected in CG1 is PEX1. Approximately 65% of the patients with PBD harbor mutations in PEX1. In the present study, we used SSCP analysis to evaluate a series of patients belonging to CG1 for mutations in PEX1 and studied phenotype-genotype correlations. A complete lack of PEX1 protein was found to be associated with severe ZS; however, residual amounts of PEX1 protein were found in patients with the milder phenotypes, NALD and IRD. The majority of these latter patients carried at least one copy of the common G843D allele. When patient fibroblasts harboring this allele were grown at 30 degrees C, a two- to threefold increase in PEX1 protein levels was observed, associated with a recovery of peroxisomal function. This suggests that the G843D missense mutation results in a misfolded protein, which is more stable at lower temperatures. We conclude that the search for the factors and/or mechanisms that determine the stability of mutant PEX1 protein by high-throughput procedures will be a first step in the development of therapeutic strategies for patients with mild PBDs.

Molecular Mechanism of a Temperature-Sensitive Phenotype in Peroxisomal Biogenesis Disorder

“…Moreover, a large proportion of Pex13p is unfolded even at a normal body temperature, but the residual adaptor activity by correctly folded proteins can somehow maintain peroxisomal functions as shown in the residual activity of the fatty acid metabolism (4,8). In PBD, TS phenotypes in Pex1, Pex2, and Pex6 with milder forms have been reported (26,27) and therapeutic effects have been reported in cells from patients with milder phenotypes, but not those with the severe phenotype, ZS (28). Treatment of PBD fibroblasts with 4-phenylbutyrate showed an induction of peroxisomes having a 2-fold increase in transcription of related genes.…”

A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 °C

“…Mutation analysis was performed as previously described for PEX1 (Walter et al 2001) and PEX12 (Gootjes et al 2004b). PEX12 nucleotides are numbered from the first ATG codon according to the mRNA sequence of GenBank, accession number NM_000286.…”

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

“…Cells were resuspended in 0.5 mL water, sonicated, and stored at −20°C. Plasmalogen synthesis was performed by TLC to comparing the microsomal incorporation of 3 H with the peroxisomal incorporation of 14 C (39).…”