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DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans


Karsai, Gergely; Kraft, Florian; Haag, Natja; Korenke, G Christoph; Hänisch, Benjamin; Othman, Alaa; Suriyanarayanan, Saranya; Steiner, Regula; Knopp, Cordula; Mull, Michael; Bergmann, Markus; Schröder, J Michael; Weis, Joachim; Elbracht, Miriam; Begemann, Matthias; Hornemann, Thorsten; Kurth, Ingo (2019). DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans. Journal of Clinical Investigation, 129(3):1229-1239.

Abstract

BACKGROUND
Sphingolipids 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.
METHODS
A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.
RESULTS
By 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.
CONCLUSION
We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.
TRIAL REGISTRATION
Not applicable.
FUNDING
Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

Abstract

BACKGROUND
Sphingolipids 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.
METHODS
A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.
RESULTS
By 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.
CONCLUSION
We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.
TRIAL REGISTRATION
Not applicable.
FUNDING
Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Scopus Subject Areas:Health Sciences > General Medicine
Language:English
Date:1 March 2019
Deposited On:24 Jul 2019 13:17
Last Modified:29 Jul 2020 10:56
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1172/JCI124159
PubMed ID:30620338

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