TY - JOUR
T1 - Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease
AU - Wegrzyn, Agnieszka B.
AU - Herzog, Katharina
AU - Gerding, Albert
AU - Kwiatkowski, Marcel
AU - Wolters, Justina C.
AU - Dolga, Amalia M.
AU - van Lint, Alida E. M.
AU - Wanders, Ronald J. A.
AU - Waterham, Hans R.
AU - Bakker, Barbara M.
PY - 2020/12
Y1 - 2020/12
N2 - 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 reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics and proteomics (available via ProteomeXchange with identifier PXD015518) data, which we obtained from healthy controls and RD patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanate and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of RD at the genome scale, and we studied the effect of phytanate on cell metabolism. We identified 53 metabolites that were predicted to discriminate between healthy and RD patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy. Databases: Transcriptomics data are available via GEO database with identifier GSE138379, and proteomics data are available via ProteomeXchange with identifier PXD015518.
AB - 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 reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics and proteomics (available via ProteomeXchange with identifier PXD015518) data, which we obtained from healthy controls and RD patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanate and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of RD at the genome scale, and we studied the effect of phytanate on cell metabolism. We identified 53 metabolites that were predicted to discriminate between healthy and RD patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy. Databases: Transcriptomics data are available via GEO database with identifier GSE138379, and proteomics data are available via ProteomeXchange with identifier PXD015518.
KW - Refsum disease
KW - amino acids
KW - fibroblast
KW - genome-scale modelling
KW - metabolism
UR - http://www.scopus.com/inward/record.url?scp=85082570743&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/febs.15292
DO - https://doi.org/10.1111/febs.15292
M3 - Article
C2 - 32160399
SN - 1742-464X
VL - 287
SP - 5096
EP - 5113
JO - FEBS journal
JF - FEBS journal
IS - 23
ER -