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DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans
Gergely Karsai, … , Thorsten Hornemann, Ingo Kurth
Gergely Karsai, … , Thorsten Hornemann, Ingo Kurth
Published January 8, 2019
Citation Information: J Clin Invest. 2019;129(3):1229-1239. https://doi.org/10.1172/JCI124159.
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Clinical Medicine Genetics Metabolism

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

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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.

Authors

Gergely Karsai, Florian Kraft, Natja Haag, G. Christoph Korenke, Benjamin Hänisch, Alaa Othman, Saranya Suriyanarayanan, Regula Steiner, Cordula Knopp, Michael Mull, Markus Bergmann, J. Michael Schröder, Joachim Weis, Miriam Elbracht, Matthias Begemann, Thorsten Hornemann, Ingo Kurth

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Figure 3

Lipidomics analysis of mutant DEGS1.

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Lipidomics analysis of mutant DEGS1.
(A) Lipidomics analysis showed a si...
(A) Lipidomics analysis showed a significant elevation of dhSL species (dhCer, dhSM, and dhHexCer) in patient plasma (P) compared with parents (F, M) or unrelated controls (C1–6). (B) Cultured patient-derived fibroblasts showed an increase in de novo–synthesized dhSL (dhCer+3 and dhSM+3) compared with cells from unrelated controls. Increased dhSL levels were also seen in DEGS1–/– HAP1 cells where the dhSL species reached up to 90% of the total SLs. In contrast, WT cells had less than 15% dhSL species. Slightly decreased dhSL levels were observed in DEGS2–/– cells. (C) Kinetics of the DEGS1 reaction in control and patient fibroblasts. Cells were supplemented with 2 μM d7SA (arrow) and the increase in total SO+7 was followed over time. Values were normalized to internal C16SO levels (ISTD). In patient-derived fibroblasts, DEGS1 activity was 5-fold lower compared with controls. This residual activity was fully inhibited in the presence of the DEGS1 inhibitor 4-HPR (2 μM). (D) The sphingoid-base profile after hydrolysis revealed an isomeric SO metabolite (arrow) with an approximately 30-second-shorter retention time. The metabolite could be detected in the patient plasma but not in plasma of the parents or unrelated controls. No isomeric peak was seen for SA (green). n = 3; data presented as the mean ±SD or –SD. ***P < 0.001 by 1-way ANOVA with Tukey’s correction for multiple testing.
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