Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
Devesh C. Pant, … , Odile Boespflug-Tanguy, Aurora Pujol
Devesh C. Pant, … , Odile Boespflug-Tanguy, Aurora Pujol
Published January 8, 2019
Citation Information: J Clin Invest. 2019;129(3):1240-1256. https://doi.org/10.1172/JCI123959.
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Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

Abstract

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients’ fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

Authors

Devesh C. Pant, Imen Dorboz, Agatha Schluter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J. Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jingmin Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky, Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N. James, Damir Musaev, Maha S. Zaki, Marc C. Patterson, Brendan C. Lanpher, Eric W. Klee, Filippo Pinto e Vairo, Elizabeth Wohler, Nara Lygia de M. Sobreira, Julie S. Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G. Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, Aurora Pujol

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Figure 6

FTY720 ameliorates the locomotor, biochemical, and cellular phenotypes in MO-DEGS1 larvae and lowers ROS levels in patient fibroblasts.

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FTY720 ameliorates the locomotor, biochemical, and cellular phenotypes i...
(A) MO-DEGS1 larvae were treated for 120 hours with vehicle (Veh) or fingolimod (FTY720) at 0.3, 1.0, and 3.3 ng/μl. Digital tracks of larvae are shown in red. (B) Scatter plot (n = 20 per condition) showing total movement distance (mm) upon FTY720 treatment. Total movement distance (mm) traveled by MO-control larvae (vehicle, 1,268.2 ± 402.9 mm; FTY720, 1,230 ± 365.2 mm), compared with MO-DEGS1 (vehicle, 44.6 ± 39.2 mm) and the different treatment doses (3.3 ng/μl FTY720, 542.3 ± 238.8 mm; 1 ng/μl FTY720, 615.3 ± 330.8 mm; 0.3 ng/μl FTY720, 670.3 ± 476.6 mm). (C) Ceramides (Cer), dihydroceramides (DhCer), and the DhCer/Cer ratios in MO-control and MO-DEGS1 zebrafish treated with 1 ng/μl FTY720 (n = 4 [5 larvae per tube/condition] larvae/condition at 5 dpf). Data are represented as percentage of total Cer and DhCer. The results are from 3 independent experiments. (D) Intracellular ROS is partially normalized by FTY720 in patient fibroblasts (n = 3) compared with controls (n = 3). Data are shown as the mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA followed by Tukey’s post hoc test.