ArticleThe Journal of clinical investigation2019
DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 128 citations in OpenAlex.
- Westernized diet related arachidonic acid metabolism expands DNA error-prone growth factor-dependent colonic quiescent stem cells in adolescent mice.Cell death & disease · 2026Article
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- Dyslipidemia is a metabolic hallmark of acute pain in sickle cell disease.medRxiv : the preprint server for health sciences · 2026Article
- Intracranial calcifications in DEGS1-Related Leukodystrophy: a potentially under-recognised neuroimaging feature.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.Human genetics · 2026Article
- Article
- Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficientFrontiers in molecular neuroscience · 2026Article
- The Involvement of Ceramide, Sphingosine-1-Phosphate and Ganglioside GM1 in Regulating Some Nervous System Functions.International journal of molecular sciences · 2025Review
- Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.American journal of human genetics · 2025Article
- Integrating omics and functional data via representation learning to prioritize candidate genes for pleiotropic effect in dairy sheep.PNAS nexus · 2025Article
- Fundamental Neurochemistry Review: Sphingolipids and Ceramides in Brain Development.Journal of neurochemistry · 2025Review
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- Ceramides in cardiovascular disease: emerging role as independent risk predictors and novel therapeutic targets.Cardiovascular research · 2025Review
- Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.The Journal of cell biology · 2025Article
- Scutellarin Alleviates Cuprizone-Induced Demyelination by Improving Mitochondrial Dysfunction, Reducing Lipid Oxidation and Inhibiting the p38 MAPK Pathway.Antioxidants (Basel, Switzerland) · 2025Article
- Dynamic Transcriptomic and Cellular Remodeling Underlie Cuprizone-Induced Demyelination and Endogenous Repair in the CNS.Antioxidants (Basel, Switzerland) · 2025Article
- Article
- Don't Be Surprised When These Surprise You: Some Infrequently Studied Sphingoid Bases, Metabolites, and Factors That Should Be Kept in Mind During Sphingolipidomic Studies.International journal of molecular sciences · 2025Review
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- Deletion Testing of theHuman mutation · 2025Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive.
methodsA combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.
resultsBy whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.
conclusionWe report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.
trial registrationNot applicable.
fundingSeventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.
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