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.
Highlights
Pseudoxanthoma elasticum (PXE) is a heritable disease arising from mutations in the ABC transporter ABCC6 and is characterized by soft tissue calcification and fragmentation manifested in the skin, eyes and cardiovascular system [1]
We describe a metabolomic profiling study showing biochemical alterations in human dermal fibroblasts of PXE patients and ABCC6-silenced cells
The identification of 358 named metabolites allowed for a thorough evaluation of differences in biochemical pathways between PXE patients and controls
Summary
Pseudoxanthoma elasticum (PXE) is a heritable disease arising from mutations in the ABC transporter ABCC6 and is characterized by soft tissue calcification and fragmentation manifested in the skin, eyes and cardiovascular system [1]. Progressive calcifications of the arterial walls can lead to cardiovascular dysfunction characterized by decreased peripheral pulses, claudication, hypertension, or coronary-artery disease with angina and/ or myocardial infarcts [6]. The prevalence of the autosomal recessive disease PXE is estimated to be between 1:25.000 and 1:100.000 [4], and to date up to 350 ABCC6 mutations were described [7] with p.R1141X (20–30%) and c.EX23_EX29del (5– 15%) being the most frequent in European PXE patients [8]
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