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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Research Article Neuroscience

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 5

Impact of degs1 knockdown in Danio rerio larvae.

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Impact of degs1 knockdown in Danio rerio larvae. (A) Ceramides (Cer), di...
(A) Ceramides (Cer), dihydroceramides (DhCer), and the DhCer/Cer ratios in MO-control and MO-DEGS1 zebrafish, n = 4/condition (5 larvae per tube/condition), at 5 dpf. Data are represented as percentage of total Cer and DhCer. (B) Representative images of the normal, mild, and severe phenotypes observed in the MO-control– and MO-DEGS1–injected groups. Scale bar: 100 μm. (C) Quantification at 5 dpf of the percentage of normal (blue), mild (purple), and severe (orange) phenotypes groups obtained. Values are the percentage ± SD of 3 independent experiments, with n = 50 animals per group per experiment. (D) Examples of digital tracks of 10 single larvae of each condition shown in red. (E) Scatter plot displaying the total movement distance by different larvae: uninjected larvae (n = 20), 1,564.4 ± 321.6 mm; MO-control (n = 30), 1,146.6 ± 255.2 mm; and MO-DEGS1 (n = 33), 28.3 ± 24.5 mm. (F–H) Dorsal views of larvae injected with MO-control and MO-DEGS1, and (I–K) inserts of boxed areas at 4.5 dpf. Scale bar: 100 μm. White arrows indicate MBP+ cells (myelinating oligodendrocytes). (L) Illustration of a tg(mbp:egfp) larva. (M) Scatter plot displaying the number of MBP+ cells in the dorsal spinal cord of 4.5-dpf larvae (MO-control, n = 30; MO-DEGS1, n = 28; MO-DEGS1 + 1 ng/μl FTY720, n = 19). Data are shown as the mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-tailed unpaired Student’s t test (A) or 1-way ANOVA followed by Tukey’s post hoc test (E and M).