title: Large-scaled metabolic profiling of human dermal fibroblasts derived from pseudoxanthoma elasticum patients and healthy controls.
abstract: Mutations in the ABC transporter ABCC6 were recently identified as cause of Pseudoxanthoma elasticum (PXE), a rare genetic disorder characterized by progressive mineralization of elastic fibers. We used an untargeted metabolic approach to identify biochemical differences between human dermal fibroblasts from healthy controls and PXE patients in an attempt to find a link between ABCC6 deficiency, cellular metabolic alterations and disease pathogenesis. 358 compounds were identified by mass spectrometry covering lipids, amino acids, peptides, carbohydrates, nucleotides, vitamins and cofactors, xenobiotics and energy metabolites. We found substantial differences in glycerophospholipid composition, leucine dipeptides, and polypeptides as well as alterations in pantothenate and guanine metabolism to be significantly associated with PXE pathogenesis. These findings can be linked to extracellular matrix remodeling and increased oxidative stress, which reflect characteristic hallmarks of PXE. Our study could facilitate a better understanding of biochemical pathways involved in soft tissue mineralization.
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kuzaj
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kuhn
authors.affiliation: Metabolon, Inc., Durham, North Carolina, United States of America.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Michalek
authors.affiliation: Metabolon, Inc., Durham, North Carolina, United States of America.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Faust
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Dabisch-Ruthe
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Knabbe
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Hendig
mesh_terms: D002114:Calcinosis / Q000473:pathology*; D002460:Cell Line; D020405:Dermis / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D004151:Dipeptides / Q000096:biosynthesis; D004547:Elastic Tissue / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000145:classification; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D020404:Glycerophospholipids / Q000096:biosynthesis / Q000145:classification; D006147:Guanine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D055432:Metabolomics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D010205:Pantothenic Acid / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011687:Purines / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D004151:Dipeptides; D005227:Fatty Acids; D020404:Glycerophospholipids; D006147:Guanine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010205:Pantothenic Acid; D011687:Purines; D034741:RNA, Small Interfering; C102029:ABCC6 protein, human