TY - JOUR AU - Pant, Devesh C. AU - Dorboz, Imen AU - Schluter, Agatha AU - Fourcade, Stéphane AU - Launay, Nathalie AU - Joya, Javier AU - Aguilera-Albesa, Sergio AU - Yoldi, Maria Eugenia AU - Casasnovas, Carlos AU - Willis, Mary J. AU - Ruiz, Montserrat AU - Ville, Dorothée AU - Lesca, Gaetan AU - Siquier-Pernet, Karine AU - Desguerre, Isabelle AU - Yan, Huifang AU - Wang, Jingmin AU - Burmeister, Margit AU - Brady, Lauren AU - Tarnopolsky, Mark AU - Cornet, Carles AU - Rubbini, Davide AU - Terriente, Javier AU - James, Kiely N. AU - Musaev, Damir AU - Zaki, Maha S. AU - Patterson, Marc C. AU - Lanpher, Brendan C. AU - Klee, Eric W. AU - Pinto e Vairo, Filippo AU - Wohler, Elizabeth AU - Sobreira, Nara Lygia de M. AU - Cohen, Julie S. AU - Maroofian, Reza AU - Galehdari, Hamid AU - Mazaheri, Neda AU - Shariati, Gholamreza AU - Colleaux, Laurence AU - Rodriguez, Diana AU - Gleeson, Joseph G. AU - Pujades, Cristina AU - Fatemi, Ali AU - Boespflug-Tanguy, Odile AU - Pujol, Aurora T1 - Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy PY - 2019/03/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI123959 VL - 129 IS - 3 UR - https://doi.org/10.1172/JCI123959 SP - 1240 EP - 1256 PB - The American Society for Clinical Investigation ER -