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J Clin Invest. 2019 Mar 1;129(3):1240-1256. doi: 10.1172/JCI123959. Epub 2019 Feb 11.

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Author information

1
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
2
Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
3
INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
4
Pediatric Neurology Unit, Department of Pediatrics, Navarra Health Service, Navarrabiomed, Pamplona, Spain.
5
Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, c/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
6
Department of Pediatrics, Naval Medical Center San Diego, San Diego, California, USA.
7
Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
8
Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, Lyon, France.
9
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
10
Developmental Brain Disorders Laboratory, INSERM UMR 1163, Paris, France.
11
Department of Pediatrics, Peking University First Hospital, Beijing, China.
12
Molecular & Behavioral Neuroscience Institute, and.
13
Departments of Computational Medicine & Bioinformatics, Psychiatry and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
14
Department of Pediatrics (Neuromuscular and Neurometabolics), McMaster Children's Hospital, Hamilton, Ontario, Canada.
15
ZeClinics SL, PRBB, Barcelona, Spain.
16
Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
17
Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
18
Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
19
Department of Clinical Genomics and.
20
Center for Individualized Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
21
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
22
McKusick-Nathans Institute of Genetic Medicine, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
23
Moser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, Maryland, USA.
24
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
25
Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
26
Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.
27
Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
28
APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France.
29
GRC ConCer-LD, Sorbonne Universités, UPMC Université, Paris, France.
30
Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
31
Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
32
Assistance Publique des Hopitaux de Paris (APHP), Reference Center for Leukodystrophies and Rare Leukoencephalopathies (LEUKOFRANCE), Hôpital Robert Debré, Paris, France.
33
Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.

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.

KEYWORDS:

Neurodegeneration; Neuroscience

PMID:
30620337
PMCID:
PMC6391109
[Available on 2019-06-01]
DOI:
10.1172/JCI123959
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