Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
Devesh C. Pant, et al.
Devesh C. Pant, et al.
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Research Article Neuroscience

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

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.

Authors

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, 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 Lygia de M. 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

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Figure 2

Schematic representation of human DEGS1 (NP_003667.1) and its functional domains with variants identified in patients.

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Schematic representation of human DEGS1 (NP_003667.1) and its functional...
(A) DEGS1 has 323 amino acids. Numbers on the scheme of the protein line indicate the boundaries of each transmembrane domain. The lipid DES domain (red) of DEGS1 comprises amino acids 6–42. The histidine domains (orange) of DEGS1 comprise amino acids 89–93, 128–132, and 259–263. The transmembrane domains (green) of DEGS1 comprise amino acids 43–62, 68–92, 104–122, 150–172, 184–202, and 210–231. The fatty acid desaturase (FAD) domain covers amino acids 64–293. (B) Schematic of the human DEGS1 locus, which consists of 3 exons. Patient (P) numbers are indicated above the mutations. Multiple protein sequence alignment of DEGS1 orthologs show conservation of missense mutations detected in cases (bottom). The lipid DES, transmembrane, and histidine domains are indicated by red, green, and orange shading, respectively. The alignment was performed with ClustalW (http://www.clustal.org/) using the following RefSeq numbers: NP_003667.1, Homo sapiens; NP_031879.1, Mus musculus; NP_445775.2, Rattus norvegicus; NP_001007485.1, Xenopus tropicalis; NP_997865.1, Danio rerio; NP_476594.1, Drosophila melanogaster; NP_493549.1, Caenorhabditis elegans.