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2019-01-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/171613

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

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https://doi.org/10.1172/JCI123959

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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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Malalties hereditàries, Neurociències

Matèries (anglès)

Genetic disorders, Neurosciences

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Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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PANT, Devesh c., DORBOZ, Imen, SCHLÜTER, Agatha, FOURCADE, Stéphane, LAUNAY, Nathalie, JOYA, Javier, AGUILERA ALBESA, Sergio, YOLDI, María eugenia, CASASNOVAS PONS, 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., PINTO E VAIRO, Filippo, WOHLER, Elizabeth, SOBREIRA, Nara lygia de m., COHEN, Julie s., MAROOFIAN, Reza, GALEHDARI, Hamid, MAZAHERI, Neda, SHARIATI, Gholamrez, COLLEAUX, Laurence, RODRIGUEZ, Diana, GLEESON, Joseph g., PUJADES, Cristina, FATEMI, Ali, BOESPFLUG‐TANGUY, Odile, PUJOL ONOFRE, Aurora. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. _Journal of Clinical Investigation_. 2019. Vol. 129, núm. 3, pàgs. 1240-1256. [consulta: 11 de abril de 2026]. [Disponible a: https://hdl.handle.net/2445/171613]

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