Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
| Autor: | Ali Al Asmari, Emmanuelle Szenker-Ravi, Carine Bonnard, Bruno Reversade, Laura Schultz-Rogers, I. Kraegeloh-Mann, Maha Abdulrahim, Hesham Aldhalaan, Byrappa Venkatesh, Célia Bosso-Lefèvre, Aida Telegrafi, Hiyam M. Marzouqa, Gunaseelan Narayanan, Sha Tang, Sonal Mahida, Melanie A. Simpson, Fowzan S. Alkuraya, Michelle Eio, Eissa Faqeih, Renske Oegema, Sarah Weckhuysen, George Grady, Joseph J. Barycki, Mohammed Al-Owain, Lamyaa A. Jad, David A. Koolen, Marjon van Slegtenhorst, Tyler Mark Pierson, Marisa V. Andrews, Rebecca Schüle, Reinhard Keimer, Amber Begtrup, Sateesh Maddirevula, Michael Muriello, Sakkubai Naidu, Damien Haye, Adel A H Mahmoud, Brian Ciruna, Abdullah Tamim, Thong Teck Tan, Rolph Pfundt, Peter Bauer, Jiin Ying Lim, Ali Awaji, Marco Tartaglia, Meral Gunay-Aygun, Eric W. Klee, Marcia C. Willing, Monica Yau, Angelika Riess, Diego Martinelli, Sabina Barresi, Sumanty Tohari, Werner Deigendesch, Dirk Lefeber, Saumya Shekhar Jamuar, Ludger Schöls, Ralitza H. Gavrilova, Alvin Yu Jin Ng, Hannah Stamberger, Suleyman Gulsuner, Adam Claridge-Chang, Élise Lebigot, Moeenaldeen Al-Sayed, Ee Shien Tan, Kagistia Hana Utami, Sarah B. Pierce, Helene Verhelst, Hankun Li, James C. Stewart, Ingo Helbig, Tal Gilboa, Mahmoud A. Pouladi, Hagar Mor-Shaked, Boris Keren, Ajay S. Mathuru, Holger Hengel, Michèl A.A.P. Willemsen, Nader Handal, Tahsin Stefan Barakat, Sulwan M. Algain, Terrence Thomas, Lance H. Rodan, Mais Hashem, Wendy G. Mitchell |
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| Přispěvatelé: | Center for Reproductive Medicine, ARD - Amsterdam Reproduction and Development, ACS - Diabetes & metabolism, Clinical Genetics, Reversade, Bruno, Hengel, H., Bosso-Lefèvre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, É., Tan, T.-T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., van Slegtenhorst, M., Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y.J., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R., Schüle, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, M.A., Jamuar, S.S., Schöls, L, School of Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Glycobiology General Physics and Astronomy VARIANTS Encephalopathy Neurodegenerative Germline 0302 clinical medicine UDP-GLUCOSE DEHYDROGENASE Loss of Function Mutation Medicine and Health Sciences EMBRYOGENESIS 2.1 Biological and endogenous factors UGDH protein human Aetiology Child lcsh:Science Zebrafish UTILITY Genetics pathology [Organoids] Multidisciplinary Uridine diphosphate glucose dehydrogenase Uridine diphosphate DP-glucuronic acid Syndrome Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Hypotonia 3. Good health Pedigree DEFICIENCY genetics [Loss of Function Mutation] Organoids genetics [Uridine Diphosphate Glucose Dehydrogenase] Child Preschool Neurological Medicine Female ddc:500 medicine.symptom Oxidoreductases Engineering sciences. Technology Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ENZYME Adolescent CONGENITAL DISORDER Science Intellectual and Developmental Disabilities (IDD) genetics [Epilepsy] chemistry [Oxidoreductases] Genetics and Molecular Biology Genes Recessive Biology Uridine Diphosphate Glucose Dehydrogenase Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Protein Domains medicine Animals Humans Recessive Clinical genetics Allele Preschool Gene Loss function Alleles HEPARAN-SULFATE Phenocopy genetics [Oxidoreductases] Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Epilepsy GLYCOSYLATION Neurosciences Infant General Chemistry biology.organism_classification medicine.disease Brain Disorders carbohydrates (lipids) Kinetics 030104 developmental biology Genes General Biochemistry Neuronal development lcsh:Q Human medicine 030217 neurology & neurosurgery Congenital disorder |
| Zdroj: | Nature communications, 11(1):595. Nature Publishing Group Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications, 11. Nature Publishing Group Nature Communications, 11 Nature communications, vol 11, iss 1 Nature Communications 11(1), 595 (2020). doi:10.1038/s41467-020-14360-7 Nature Communications, 11, 1 Nature communications Nature Communications NATURE COMMUNICATIONS |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-14360-7 |
| Popis: | Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy. German Research Foundation (DFG); European Union (European Union); NEUROMICS Network; International Coordination Action (ICA); Fund for Scientific Research Flanders (FWO); Netherlands Organization for Scientific Research (ZONMW VIDI); National Medical Research Council, Singapore; A Strategic Positioning Fund on Genetic Orphan Diseases (GODAFIT); Industry Alignment Fund on Singapore Childhood Undiagnosed Diseases Program (SUREKids); Biomedical Research Council, A*STAR; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases; Fondazione Bambino Gesù (Vite Coraggiose); Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Eurocores Program EuroEPINOMICS; University of Antwerp Research Fund; FRAXA Foundation; Brain & Behavior Research Foundation, NARSAD Young Investigator Grant |
| Databáze: | OpenAIRE |
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