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Title: Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
Author: Pant, Devesh C.
Dorboz, Imen
Schlüter, Agatha
Fourcade, Stéphane
Launay, Nathalie
Joya, Javier
Aguilera Albesa, Sergio
Yoldi, Maria Eugenia
Casasnovas Pons, Carlos
Willis, Mary J.
Ruiz, Montserrat
Ville, Dorothée
Lesca, Gaetan
Siquier Pernet, Karine
Desguerre, Isabelle
Yan, Huifang
Wang, Jingmin
Burmeister, Margit
Brady, Lauren
Tarnopolsky, Mark
Cornet, Carles
Rubbini, Davide
Terriente, Javier
James, Kiely N.
Musaev, Damir
Zaki, Maha S.
Patterson, Marc C.
Lanpher, Brendan C.
Klee, Eric W.
Pinto e Vairo, Filippo
Wohler, Elizabeth
Sobreira, Nara Lygia de M.
Cohen, Julie S.
Maroofian, Reza
Galehdari, Hamid
Mazaheri, Neda
Shariati, Gholamrez
Colleaux, Laurence
Rodriguez, Diana
Gleeson, Joseph G.
Pujades, Cristina
Fatemi, Ali
Boespflug‐Tanguy, Odile
Pujol Onofre, Aurora
Keywords: Malalties hereditàries
Genetic disorders
Issue Date: 1-Jan-2019
Publisher: American Society for Clinical Investigation
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.
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It is part of: Journal of Clinical Investigation, 2019, vol. 129, num. 3, p. 1240-1256
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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