Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

Devesh C. Pant, Imen Dorboz, Agatha Schluter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J. Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jingmin Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky & 24 others Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N. James, Damir Musaev, Maha S. Zaki, Marc C. Patterson, Brendan C. Lanpher, Eric W. Klee, Filippo Pinto E Vairo, Elizabeth Wohler, Nara Sobreira, Julie S. Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G. Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, Aurora Pujol

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1240-1256
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number3
DOIs
StatePublished - Mar 1 2019

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Ceramides
Zebrafish
Myelin Sheath
Exome
Leukoencephalopathies
Failure to Thrive
Sphingolipids
Critical Pathways
Dystonia
Corpus Callosum
Oligodendroglia
Endoplasmic Reticulum
Multiple Sclerosis
Atrophy
Fibroblasts
Maintenance
Lipids
Muscles
dihydroceramide
Fingolimod Hydrochloride

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pant, D. C., Dorboz, I., Schluter, A., Fourcade, S., Launay, N., Joya, J., ... Pujol, A. (2019). Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. Journal of Clinical Investigation, 129(3), 1240-1256. https://doi.org/10.1172/JCI123959

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. / Pant, Devesh C.; Dorboz, Imen; Schluter, Agatha; Fourcade, Stéphane; Launay, Nathalie; Joya, Javier; Aguilera-Albesa, Sergio; Yoldi, Maria Eugenia; Casasnovas, 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.; E Vairo, Filippo Pinto; Wohler, Elizabeth; Sobreira, Nara; Cohen, Julie S.; Maroofian, Reza; Galehdari, Hamid; Mazaheri, Neda; Shariati, Gholamreza; Colleaux, Laurence; Rodriguez, Diana; Gleeson, Joseph G.; Pujades, Cristina; Fatemi, Ali; Boespflug-Tanguy, Odile; Pujol, Aurora.

In: Journal of Clinical Investigation, Vol. 129, No. 3, 01.03.2019, p. 1240-1256.

Research output: Contribution to journalArticle

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, E Vairo, FP, Wohler, E, Sobreira, N, 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', Journal of Clinical Investigation, vol. 129, no. 3, pp. 1240-1256. https://doi.org/10.1172/JCI123959
Pant DC, Dorboz I, Schluter A, Fourcade S, Launay N, Joya J et al. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. Journal of Clinical Investigation. 2019 Mar 1;129(3):1240-1256. https://doi.org/10.1172/JCI123959
Pant, Devesh C. ; Dorboz, Imen ; Schluter, Agatha ; Fourcade, Stéphane ; Launay, Nathalie ; Joya, Javier ; Aguilera-Albesa, Sergio ; Yoldi, Maria Eugenia ; Casasnovas, 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. ; E Vairo, Filippo Pinto ; Wohler, Elizabeth ; Sobreira, Nara ; Cohen, Julie S. ; Maroofian, Reza ; Galehdari, Hamid ; Mazaheri, Neda ; Shariati, Gholamreza ; Colleaux, Laurence ; Rodriguez, Diana ; Gleeson, Joseph G. ; Pujades, Cristina ; Fatemi, Ali ; Boespflug-Tanguy, Odile ; Pujol, Aurora. / Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 3. pp. 1240-1256.
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AU - Joya, Javier

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AU - Brady, Lauren

AU - Tarnopolsky, Mark

AU - Cornet, Carles

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AU - James, Kiely N.

AU - Musaev, Damir

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AU - Patterson, Marc C.

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AU - Klee, Eric W.

AU - E Vairo, Filippo Pinto

AU - Wohler, Elizabeth

AU - Sobreira, Nara

AU - Cohen, Julie S.

AU - Maroofian, Reza

AU - Galehdari, Hamid

AU - Mazaheri, Neda

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AU - Colleaux, Laurence

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AU - Gleeson, Joseph G.

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