TY - JOUR
T1 - Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
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 - E Vairo, Filippo Pinto
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
N1 - Publisher Copyright:
Copyright 2019, American Society for Clinical Investigation.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
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.
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U2 - 10.1172/JCI123959
DO - 10.1172/JCI123959
M3 - Article
C2 - 30620337
AN - SCOPUS:85062412118
SN - 0021-9738
VL - 129
SP - 1240
EP - 1256
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
ER -