Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

A knockdown approach for disease modeling in zebrafish, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod.

Devesh C Pant 1 2Imen Dorboz 3Agatha Schluter 1 2Stéphane Fourcade 1 2Nathalie Launay 1 2Javier Joya 1 2Sergio Aguilera-Albesa 4Maria Eugenia Yoldi 4Carlos Casasnovas 1 2 5Mary J Willis 6Montserrat Ruiz 1 2Dorothée Ville 7Gaetan Lesca 8Karine Siquier-Pernet 9 10Isabelle Desguerre 9 10Huifang Yan 11 12Jingmin Wang 11Margit Burmeister 12 13Lauren Brady 14Mark Tarnopolsky 14Carles Cornet 15Davide Rubbini 15Javier Terriente 15Kiely N James 16Damir Musaev 16Maha S Zaki 17Marc C Patterson 18Brendan C Lanpher 19Eric W Klee 19 20Filippo Pinto E Vairo 19 20Elizabeth Wohler 21Nara Lygia de M Sobreira 22Julie S Cohen 23Reza Maroofian 24Hamid Galehdari 25Neda Mazaheri 25 26Gholamreza Shariati 26 27Laurence Colleaux 9 10Diana Rodriguez 28 29Joseph G Gleeson 16Cristina Pujades 30Ali Fatemi 23 31Odile Boespflug-Tanguy 3 32Aurora Pujol 1 2 33

1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

2Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.

3INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, Paris, France.

4Pediatric Neurology Unit, Department of Pediatrics, Navarra Health Service, Navarrabiomed, Pamplona, Spain.

5Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, c/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.

6Department of Pediatrics, Naval Medical Center San Diego, San Diego, California, USA.

7Department of Neuropediatrics, Lyon University Hospital, Lyon, France.

8Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, Lyon, France.

9Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.

10Developmental Brain Disorders Laboratory, INSERM UMR 1163, Paris, France.

11Department of Pediatrics, Peking University First Hospital, Beijing, China.

12Molecular & Behavioral Neuroscience Institute, and.

13Departments of Computational Medicine & Bioinformatics, Psychiatry and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

14Department of Pediatrics (Neuromuscular and Neurometabolics), McMaster Children's Hospital, Hamilton, Ontario, Canada.

15ZeClinics SL, PRBB, Barcelona, Spain.

16Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.

17Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.

18Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.

19Department of Clinical Genomics and.

20Center for Individualized Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

21McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

22McKusick-Nathans Institute of Genetic Medicine, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

23Moser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, Maryland, USA.

24Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.

25Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.

26Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.

27Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

28APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France.

29GRC ConCer-LD, Sorbonne Universités, UPMC Université, Paris, France.

30Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.

31Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

32Assistance Publique des Hopitaux de Paris (APHP), Reference Center for Leukodystrophies and Rare Leukoencephalopathies (LEUKOFRANCE), Hôpital Robert Debré, Paris, France.

33Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.



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.

Ver medio View full article The Journal of Clinical Investigation