Dataset Information

A fibroblast-specific genome-scale model focused on fatty acid alpha-oxidation

ABSTRACT: Refsum disease is an inborn error of metabolism that is characterized by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. After clinical suspicion of this disorder, including progressive retinitis pigmentosa and polyneuropathy, Refsum disease is biochemically diagnosed by elevated levels of phytanic acid in plasma and tissues of the patient. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet. In recent years, computational models have become valuable tools to provide insight into the complex behaviour of metabolic networks. Besides the comprehensive models that contain all known metabolic reactions within the human body, several tissue- and cell-type-specific models have been developed. However, while systems biology approaches are widely used for complex diseases, only few studies have been published for inborn errors of metabolism. In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics, exo-metabolomics, and proteomics data, which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome scale, and we studied the effect of phytanic acid on cell metabolism. We identified 20 metabolites that were predicted to discriminate between Healthy and Refsum’s Disease patients, whereof several with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

OTHER RELATED OMICS DATASETS IN: GSE138379

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Refsum Disease

SUBMITTER: Justina C. Wolters

LAB HEAD: Wolters JC

PROVIDER: PXD015518 | Pride | 2020-03-20

REPOSITORIES: Pride

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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease.

Wegrzyn Agnieszka B AB Herzog Katharina K Gerding Albert A Kwiatkowski Marcel M Wolters Justina C JC Dolga Amalia M AM van Lint Alida E M AEM Wanders Ronald J A RJA Waterham Hans R HR Bakker Barbara M BM

The FEBS journal 20200331 23

Refsum disease (RD) is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanate in plasma and tissues of patients. To date, no cure exists for RD, but phytanate levels in patients can be reduced by plasmapheresis and a strict diet. In this study, we reconstruct ...[more]

PMID: 32160399

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