Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Pant, DC; Dorboz, I; Schluter, A; Fourcade, S; Launay, N; Joya, J; Aguilera-Albesa, S; Yoldi, ME; Casasnovas, C; Willis, MJ; et al. Pant, DC; Dorboz, I; Schluter, A; Fourcade, S; Launay, N; Joya, J; Aguilera-Albesa, S; Yoldi, ME; Casasnovas, C; Willis, MJ; Ruiz, M; Ville, D; Lesca, G; Siquier-Pernet, K; Desguerre, I; Yan, H; Wang, J; Burmeister, M; Brady, L; Tarnopolsky, M; Cornet, C; Rubbini, D; Terriente, J; James, KN; Musaev, D; Zaki, MS; Patterson, MC; Lanpher, BC; Klee, EW; Vairo, FPE; Wohler, E; de M Sobreira, NL; Cohen, JS; Maroofian, R; Galehdari, H; Mazaheri, N; Shariati, G; Colleaux, L; Rodriguez, D; Gleeson, JG; Pujades, C; Fatemi, A; Boespflug-Tanguy, O; Pujol, A (2019) Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest, 129 (3). pp. 1240-1256. ISSN 1558-8238
SGUL Authors: Maroofian, Reza

PDF Published Version
Available under License ["licenses_description_publisher" not defined].

Download (7MB) | Preview
[img] PDF Accepted Version
Restricted to Repository staff only
Available under License ["licenses_description_publisher" not defined].

Download (1MB)


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.

Item Type: Article
Additional Information: Copyright © 2019, American Society for Clinical Investigation
Keywords: Neurodegeneration, Neuroscience, 11 Medical And Health Sciences, Immunology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Clin Invest
ISSN: 1558-8238
Language: eng
1 March 2019Published
11 February 2019Published Online
21 December 2018Accepted
Publisher License: Publisher's own licence
Project IDFunderFunder ID
FIS PI14/00581Instituto de Salud Carlos III
345/C/2014‘La Marató de TV3’ FoundationUNSPECIFIED
ACCI14-759Hesperia FoundationUNSPECIFIED
2017SGR1206Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of CataloniaUNSPECIFIED
BFU2015-67400-PSpanish Ministry of Economy and CompetitivenessUNSPECIFIED
CPII16/00016Spanish Institute for Health Carlos IIIUNSPECIFIED
FI-DGR 2014Government of CataloniaUNSPECIFIED
ANR-10-IAHU-01National Research AgencyUNSPECIFIED
DEQ20160334938Fondation pour la Recherche Médicale
2009-007I4AV2Seventh Framework Programme
P01HD070494National Institutes of Health
1R01NS098004National Institutes of Health
R01NS048453National Institutes of Health
R01NS052455National Institutes of Health
UL1TR001866National Institutes of Health
275275Simons Foundation
6-1463-3-351Qatar National Research FoundationUNSPECIFIED
5UM1HG006504Yale University Center for Mendelian GenomicsUNSPECIFIED
5UM1HG008900Broad InstituteUNSPECIFIED
1U54 HG006542National Institutes of Health
1U54HG006493National Human Genome Research Institute
U54 HD079123National Institute of Child Health and Human Development
NS056780National Institutes of Health
65768-01National Institutes of Health
PubMed ID: 30620337
Go to PubMed abstract
Publisher's version:

Actions (login required)

Edit Item Edit Item