Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders

Abstract

The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), are autosomal recessive diseases caused by deficiency of peroxisome assembly as well as malfunction of peroxisomes, where >10 genotypes have been reported. ZS patients manifest the most severe clinical and biochemical abnormalities, while those with NALD and IRD show the least severity and the mildest features, respectively. PEX1 is the causative gene for PBDs of complementation group I (CG1), the highest incidence PBD, and encodes the peroxin, Pex1p, a member of the AAA ATPase family. In the present work, we found that peroxisomes were morphologically and biochemically formed at 30 but not 37 degrees C, in the fibroblasts from all CG1 IRD patients examined, whereas almost no peroxisomes were seen in ZS and NALD cells, even at 30 degrees C. A point missense mutation, G843D, was identified in the PEX1 allele of most CG1 IRD patients. The mutant PEX1, termed HsPEX1G843D, gave rise to the same temperature-sensitive phenotype on CG1 CHO cell mutants upon transfection. Collectively, these results demonstrate temperature-sensitive peroxisome assembly to be responsible for the mildness of the clinical features of PEX1 -defective IRD of CG1.

Temperature-Sensitive Mutation of PEX6 in Peroxisome Biogenesis Disorders in Complementation Group C (CG-C): Comparative Study of PEX6 and PEX1

“…In previous studies, we revealed the restoration of peroxisomes in a temperature-dependent manner in the fibroblasts of patients with milder types of PBD, those with all types of IRD, and some with the NALD phenotype in CG-E (CG1), CG-A (CG8), CG-F (CG10), and CG-H. In addition, we demonstrated ts mutations that cause this phenomenon in IRD and NALD patients with CG-E (CG1), CG-F (CG10), and CG-H; G843D in PEX1, E55K in PEX2, and I326T in PEX13, respectively (18,23,24). We have now identified a missense mutation in PEX6 from a NALD patient with CG-C (CG4) whose fibroblasts revealed the same ts phenotype.…”

“…Similarly, an IRD patient (E-06) from CG-E (CG1) was homozygous for a ts mutation in PEX1, leading to a G843D amino acid substitution (24). Interaction between PEX6 and PEX1 for peroxisome biogenesis has been reported in both yeast and humans (29 -32).…”

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

“…The subcellular localization (diffuse cytosolic or punctate peroxisomal) was visualized with fluorescence microscopy studies (Mandel et al 1994;Roels et al 2003). The second is temperature sensitivity, the restoration of morphological peroxisome formation and peroxisomal biochemical function in PBD fibroblasts cultured at 30°C rather than 37°C (Hashimoto et al 2005;Imamura et al 1998;Osumi et al 2000). It has been suggested that temperature sensitivity is a consequence of an imbalance of folding and unfolding kinetics of mutant proteins, resulting in a reduction of correctly folded protein as temperature increases (Hashimoto et al 2005).…”

Infantile Refsum Disease: Influence of Dietary Treatment on Plasma Phytanic Acid Levels

“…In addition, this pathogenic variant influences the PEX1 activity in a temperature-sensitive manner, i.e. while at 37 C import of matrix proteins into "ghost" peroxisomes is observed in some cells (peroxisomal mosaicism), at 30 C, peroxisomal import is almost completely recovered, as well as peroxisomal metabolic functions, and at 40 C, no peroxisomal import is observed (Imamura et al 1998). Overall, this pathogenic variant retains a residual peroxisomal function which, along with peroxisomal mosaicism, results in less severe biochemical deficiencies, a milder clinical phenotype and prolonged survival (Osumi et al 2000;Poll-The et al 2004;Crane et al 2005).…”