Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

A knockdown approach for disease modeling in zebrafish, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod.

Devesh C Pant 1 2Imen Dorboz 3Agatha Schluter 1 2Stéphane Fourcade 1 2Nathalie Launay 1 2Javier Joya 1 2Sergio Aguilera-Albesa 4Maria Eugenia Yoldi 4Carlos Casasnovas 1 2 5Mary J Willis 6Montserrat Ruiz 1 2Dorothée Ville 7Gaetan Lesca 8Karine Siquier-Pernet 9 10Isabelle Desguerre 9 10Huifang Yan 11 12Jingmin Wang 11Margit Burmeister 12 13Lauren Brady 14Mark Tarnopolsky 14Carles Cornet 15Davide Rubbini 15Javier Terriente 15Kiely N James 16Damir Musaev 16Maha S Zaki 17Marc C Patterson 18Brendan C Lanpher 19Eric W Klee 19 20Filippo Pinto E Vairo 19 20Elizabeth Wohler 21Nara Lygia de M Sobreira 22Julie S Cohen 23Reza Maroofian 24Hamid Galehdari 25Neda Mazaheri 25 26Gholamreza Shariati 26 27Laurence Colleaux 9 10Diana Rodriguez 28 29Joseph G Gleeson 16Cristina Pujades 30Ali Fatemi 23 31Odile Boespflug-Tanguy 3 32Aurora Pujol 1 2 33


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.

Ver medio View full article The Journal of Clinical Investigation

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