Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder

Kevin Berendse,Lodewijk Ijlst,Ronaldj A Wanders,Bwee Tien Poll-The,Merel S Ebberink,Hans R Waterham

doi:10.1186/1750-1172-8-138

Abstract

BackgroundZellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. The phenotypic spectrum of ZSDs ranges from an early lethal form to much milder presentations. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern. This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. In cell lines displaying peroxisomal mosaicism, peroxisome biogenesis can be improved when these are cultured at 30°C. This suggests that these missense mutations affect the folding and/or stability of the encoded protein. We have studied if the function of mutant PEX1, PEX6 and PEX12 can be improved by promoting protein folding using the chemical chaperone arginine.MethodsFibroblasts from three PEX1 patients, one PEX6 and one PEX12 patient were cultured in the presence of different concentrations of arginine. To determine the effect on peroxisome biogenesis we studied the following parameters: number of peroxisome-positive cells, levels of PEX1 protein and processed thiolase, and the capacity to β-oxidize very long chain fatty acids and pristanic acid.ResultsPeroxisome biogenesis and function in fibroblasts with mild missense mutations in PEX1, 6 and 12 can be improved by arginine.ConclusionArginine may be an interesting compound to promote peroxisome function in patients with a mild peroxisome biogenesis disorder.

Highlights

Zellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis
We studied the effect of arginine on peroxisome biogenesis and functioning in primary fibroblasts carrying mild mutations in PEX1, PEX6 or PEX12
We observed significant increases in the number of peroxisome-positive cells among fibroblasts supplemented with arginine compared to untreated fibroblasts (Figure 1 and Additional file 1: Figure S1)

Summary

Introduction

Zellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. When skin fibroblasts from milder patients are cultured at 37°C and examined for the localization of the peroxisomal matrix protein catalase, a mixed population of cells with either catalase-containing or catalase-lacking peroxisomes can be seen [5,6,7] This phenomenon is called peroxisomal mosaicism and has been described for mutations in various PEX genes (e.g. PEX1, PEX2, PEX6, PEX10 and PEX12), which are associated with a relatively mild phenotype [5,6,8,9]

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Conclusion