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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.

SUBMITTER: Pant DC 

PROVIDER: S-EPMC6391109 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Pant Devesh C DC   Dorboz Imen I   Schluter Agatha A   Fourcade Stéphane S   Launay Nathalie N   Joya Javier J   Aguilera-Albesa Sergio S   Yoldi Maria Eugenia ME   Casasnovas Carlos C   Willis Mary J MJ   Ruiz Montserrat M   Ville Dorothée D   Lesca Gaetan G   Siquier-Pernet Karine K   Desguerre Isabelle I   Yan Huifang H   Wang Jingmin J   Burmeister Margit M   Brady Lauren L   Tarnopolsky Mark M   Cornet Carles C   Rubbini Davide D   Terriente Javier J   James Kiely N KN   Musaev Damir D   Zaki Maha S MS   Patterson Marc C MC   Lanpher Brendan C BC   Klee Eric W EW   Pinto E Vairo Filippo F   Wohler Elizabeth E   Sobreira Nara Lygia de M NLM   Cohen Julie S JS   Maroofian Reza R   Galehdari Hamid H   Mazaheri Neda N   Shariati Gholamreza G   Colleaux Laurence L   Rodriguez Diana D   Gleeson Joseph G JG   Pujades Cristina C   Fatemi Ali A   Boespflug-Tanguy Odile O   Pujol Aurora A  

The Journal of clinical investigation 20190211 3


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  ...[more]

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