ArticleThe Journal of clinical investigation2019
Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.
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Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 103 citations in OpenAlex.
- Whole-exome sequencing reveals novel and previously reported variants in genes linked to white matter pathology in neurodevelopmental disorders.European journal of human genetics : EJHG · 2026Article
- Intracranial calcifications in DEGS1-Related Leukodystrophy: a potentially under-recognised neuroimaging feature.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.Human genetics · 2026Article
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- Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficientFrontiers in molecular neuroscience · 2026Article
- The Involvement of Ceramide, Sphingosine-1-Phosphate and Ganglioside GM1 in Regulating Some Nervous System Functions.International journal of molecular sciences · 2025Review
- Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.American journal of human genetics · 2025Article
- Fundamental Neurochemistry Review: Sphingolipids and Ceramides in Brain Development.Journal of neurochemistry · 2025Review
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- Dysregulated miRNAs Targeting Adiponectin Signaling in Colorectal Cancer.International journal of molecular sciences · 2025Review
- Regulation of CNS Lipids by Protease Activated Receptor 1.Journal of neurochemistry · 2025Article
- Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population.American journal of medical genetics. Part A · 2025Article
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- Deletion Testing of theHuman mutation · 2025Article
- Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.Communications biology · 2024Article
- Overview of Neuro-Ophthalmic Findings in Leukodystrophies.Journal of clinical medicine · 2024Article
- Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.Molecular genetics and genomics : MGG · 2024Article
- GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice.Molecular neurodegeneration · 2024Article
- Re-evaluation and re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 18.European journal of human genetics : EJHG · 2023Article
- 3' UTR Deletion ofGenes · 2023Article
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Authors and funding
44 authors at 20 institutions in 9 countries.
Devesh C PantNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Imen DorbozINSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
Agatha SchluterNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Stéphane FourcadeNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Nathalie LaunayNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Javier JoyaNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Sergio Aguilera-AlbesaPediatric Neurology Unit, Department of Pediatrics, Navarra Health Service, Navarrabiomed, Pamplona, Spain.
Maria Eugenia YoldiPediatric Neurology Unit, Department of Pediatrics, Navarra Health Service, Navarrabiomed, Pamplona, Spain.
Carlos CasasnovasNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Mary J WillisDepartment of Pediatrics, Naval Medical Center San Diego, San Diego, California, USA.
Montserrat RuizNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Dorothée VilleDepartment of Neuropediatrics, Lyon University Hospital, Lyon, France.
Gaetan LescaDepartment of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, Lyon, France.
Karine Siquier-PernetParis Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Isabelle DesguerreParis Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Huifang YanDepartment of Pediatrics, Peking University First Hospital, Beijing, China.
Jingmin WangDepartment of Pediatrics, Peking University First Hospital, Beijing, China.
Margit BurmeisterMolecular & Behavioral Neuroscience Institute, and.
Lauren BradyDepartment of Pediatrics (Neuromuscular and Neurometabolics), McMaster Children's Hospital, Hamilton, Ontario, Canada.
Mark TarnopolskyDepartment of Pediatrics (Neuromuscular and Neurometabolics), McMaster Children's Hospital, Hamilton, Ontario, Canada.
Carles CornetZeClinics SL, PRBB, Barcelona, Spain.
Davide RubbiniZeClinics SL, PRBB, Barcelona, Spain.
Javier TerrienteZeClinics SL, PRBB, Barcelona, Spain.
Kiely N JamesLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
Damir MusaevLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
Maha S ZakiHuman Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
Marc C PattersonDepartments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
Brendan C LanpherDepartment of Clinical Genomics and.
Eric W KleeDepartment of Clinical Genomics and.
Filippo Pinto E VairoDepartment of Clinical Genomics and.
Elizabeth WohlerMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nara Lygia de M SobreiraMcKusick-Nathans Institute of Genetic Medicine, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Julie S CohenMoser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, Maryland, USA.
Reza MaroofianGenetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
Hamid GalehdariDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Neda MazaheriDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Gholamreza ShariatiNarges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.
Laurence ColleauxParis Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Diana RodriguezAPHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France.
Joseph G GleesonLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
Cristina PujadesDepartment of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Ali FatemiMoser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, Maryland, USA.
Odile Boespflug-TanguyINSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
Aurora PujolNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
Instituto de Salud Carlos III · ESDélégation Paris 5 · FRHoward Hughes Medical Institute · USMayo Clinic · USZeClinics (Spain) · ESInserm · FRJohns Hopkins University · USKennedy Krieger Institute · USMcMaster Children's Hospital · CANavarrabiomed · ESPeking University · CNShahid Chamran University of Ahvaz · IRAhvaz Jundishapur University of Medical Sciences · IRHospices Civils de Lyon · FRInstitució Catalana de Recerca i Estudis Avançats · ESNational Research Centre · EGNaval Medical Center San Diego · USSorbonne Université · FRSt George's, University of London · GBUniversitat Pompeu Fabra · ES
Funding
Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MUW Center for Mendelian GenomicsU54HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, NICKERSON, DEBORAH A · 2012 to 2015
$20.0MTraining & EducationU54NS065768 · NINDS · UNIVERSITY OF MINNESOTA · PI WHITLEY, CHESTER B. · 2009 to 2024
$17.7MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBaylor-Johns Hopkins Center for Mendelian GeneticsU54HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2012 to 2015
$15.6MYale Center for Mendelian GenomicsUM1HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2016 to 2020
$14.8MSleep and Circadian Dysfunction, Brain and Neurobehavioral Development in AutismP50HD103538 · NICHD · HUGO W. MOSER RES INST KENNEDY KRIEGER · PI S. Ali Fatemi, Bradley L Schlaggar · 2020 to 2026
$9.9MTranslational Neuroscience CoreU54HD079123 · NICHD · HUGO W. MOSER RES INST KENNEDY KRIEGER · PI FATEMI, S. ALI · 2014 to 2019
$7.9MProject 3. Genetic Models of Human Structural Brain Defects in ZebrafishP01HD070494 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2011 to 2016
$6.7MMolecular Characterization of Joubert SyndromeR01NS048453 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2004 to 2020
$6.0MMolecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6MJouberin and Nephrocystin in Joubert SyndromeR01NS052455 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2007 to 2015
$3.0MCIHRHoward Hughes Medical InstituteNCATS NIH HHS UL1 TR001866NHGRI NIH HHS U54 HG006493NHGRI NIH HHS U54 HG006542NHGRI NIH HHS UM1 HG006504NHGRI NIH HHS UM1 HG008900NICHD NIH HHS P01 HD070494NICHD NIH HHS P50 HD103538NICHD NIH HHS U54 HD079123NIH HHS S10 OD018521NINDS NIH HHS F31 NS056780NINDS NIH HHS R01 NS048453NINDS NIH HHS R01 NS052455NINDS NIH HHS R01 NS098004NINDS NIH HHS U54 NS065768
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.
Indexed as
Animals, Genetically ModifiedBrainHereditary Central Nervous System Demyelinating DiseasesZebrafishZebrafish ProteinsAnimalsDisease Models, AnimalFatty Acid DesaturasesFingolimod HydrochlorideHumansLocomotionOligodendrogliaDEGS1 protein, humanFatty Acid DesaturasesFingolimod HydrochlorideZebrafish ProteinsNeurodegenerationNeuroscience
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