2. Academic Validation
  3. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

  • Nat Commun. 2020 Jan 30;11(1):595. doi: 10.1038/s41467-020-14360-7.
Holger Hengel # 1 2,  Célia Bosso-Lefèvre # 3 4,  George Grady 5,  Emmanuelle Szenker-Ravi 3,  Hankun Li 6,  Sarah Pierce 7,  Élise Lebigot 8,  Thong-Teck Tan 9,  Michelle Y Eio 9,  Gunaseelan Narayanan 9,  Kagistia Hana Utami 10,  Monica Yau 11,  Nader Handal 12,  Werner Deigendesch 12,  Reinhard Keimer 13,  Hiyam M Marzouqa 12,  Meral Gunay-Aygun 14,  Michael J Muriello 14,  Helene Verhelst 15,  Sarah Weckhuysen 16 17 18,  Sonal Mahida 19,  Sakkubai Naidu 19,  Terrence G Thomas 20,  Jiin Ying Lim 21 22 23,  Ee Shien Tan 21 22 23,  Damien Haye 24,  Michèl A A P Willemsen 25,  Renske Oegema 26,  Wendy G Mitchell 27,  Tyler Mark Pierson 28,  Marisa V Andrews 29,  Marcia C Willing 29,  Lance H Rodan 30,  Tahsin Stefan Barakat 31,  Marjon van Slegtenhorst 31,  Ralitza H Gavrilova 32,  Diego Martinelli 33,  Tal Gilboa 34,  Abdullah M Tamim 35,  Mais O Hashem 36,  Moeenaldeen D AlSayed 37,  Maha M Abdulrahim 37,  Mohammed Al-Owain 37,  Ali Awaji 38,  Adel A H Mahmoud 39,  Eissa A Faqeih 40,  Ali Al Asmari 40,  Sulwan M Algain 41,  Lamyaa A Jad 39,  Hesham M Aldhalaan 42,  Ingo Helbig 43,  David A Koolen 44,  Angelika Riess 45,  Ingeborg Kraegeloh-Mann 46,  Peter Bauer 45,  Suleyman Gulsuner 7,  Hannah Stamberger 16 17 18,  Alvin Yu Jin Ng 47,  Sha Tang 48,  Sumanty Tohari 47,  Boris Keren 49,  Laura E Schultz-Rogers 32,  Eric W Klee 32,  Sabina Barresi 33,  Marco Tartaglia 33,  Hagar Mor-Shaked 50,  Sateesh Maddirevula 36,  Amber Begtrup 51,  Aida Telegrafi 51,  Rolph Pfundt 44,  Rebecca Schüle 1 2,  Brian Ciruna 11,  Carine Bonnard 3,  Mahmoud A Pouladi 10 52 53,  James C Stewart 47,  Adam Claridge-Chang 47 54,  Dirk J Lefeber 55 56,  Fowzan S Alkuraya 36,  Ajay S Mathuru 6 47,  Byrappa Venkatesh 4 47,  Joseph J Barycki 5,  Melanie A Simpson 5,  Saumya S Jamuar 21 22 23 57,  Ludger Schöls 58 59,  Bruno Reversade 60 61 62 63 64
Affiliations

Affiliations

  • 1 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 2 German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • 3 Institute of Medical Biology, A*STAR, Biopolis, Singapore, 138648, Singapore.
  • 4 National University of Singapore, Department of Paediatrics, Yong Loo Lin School of Medicine, Biopolis, Singapore, Singapore.
  • 5 Department of Molecular and Structural Biochemistry North Carolina State University, Raleigh, NC, 27607, USA.
  • 6 Yale-NUS College, 12 College Avenue West, Biopolis, Singapore, Singapore.
  • 7 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • 8 Service De Biochimie, Hopital Bicêtre, Assistance publique-Hôpitaux de Paris, 78 avenue du general leclerc, Le Kremlin Bicêtre, France.
  • 9 Institute of Medical Biology, Singapore Stem Cell Bank, A∗STAR, Biopolis, Singapore, 138648, Singapore.
  • 10 Translational Laboratory in Genetic Medicine, Agency for Science, Technology, and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore.
  • 11 Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics, The University of Toronto, Toronto, ON, Canada.
  • 12 Caritas Baby Hospital Bethlehem, Bethlehem, State of Palestine.
  • 13 Ped Neurology, Staufer Hospital, Wetzgauer Straße 85, Schwäbisch-Gmünd, Germany.
  • 14 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • 15 Department of Paediatric Neurology, Ghent University Hospital, Ghent, Belgium.
  • 16 Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • 17 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 18 Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
  • 19 Division of Neurology and Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 20 Neurology Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Singapore.
  • 21 Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Singapore.
  • 22 Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
  • 23 SingHealth Duke-NUS Genomic Medicine Centre, Singapore, Singapore.
  • 24 Service de Génétique Médicale, CHU De Nice Hôpital de l'Archet 2, 151 route Saint Antoine de la Ginestière, CS 23079 062002, Nice, Cedex 3, France.
  • 25 Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 26 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 27 Neurology Division, Childrens Hospital Los Angeles & Department of Neurology, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90033, USA.
  • 28 Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 29 Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  • 30 Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 31 Department of Clinical Genetics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
  • 32 Department of Clinical Genomics, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
  • 33 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, 00146, Rome, Italy.
  • 34 Child Neurology Unit, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • 35 Pediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 36 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 37 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 38 Department of Pediatrics, King Fahad Central Hospital in Jizan, Abu Arish, Saudi Arabia.
  • 39 Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 40 Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 41 General Pediatrics and Adolescents, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 42 Neuroscience Department King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 43 Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 44 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 45 Institute of Medical Genetics and Applied Genomics (Tübingen) and Centogene AG (Rostock), Rostock, Germany.
  • 46 Department of Pediatric Neurology, University of Tübingen, Tübingen, Germany.
  • 47 Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673, Singapore.
  • 48 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 49 APHP, GH Pitié Salpêtrière, Department of Genetics, Unit of Development Genomics, Paris, France.
  • 50 Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • 51 GeneDx, 207 Perry Parkway, Gaithersburg, MD, 20877, USA.
  • 52 Department of Physiology, National University of Singapore, Singapore, 117597, Singapore.
  • 53 Department of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • 54 Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, Singapore.
  • 55 Department of Neurology, Donders Center for Brain, Cognition, and Behavior, Nijmegen, The Netherlands.
  • 56 Department of Laboratory Medicine, Translational Metabolic Laboratory, Nijmegen, The Netherlands.
  • 57 SingHealth Duke-NUS Institute of Precision Medicine, Singapore, Singapore.
  • 58 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [email protected].
  • 59 German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany. [email protected].
  • 60 Institute of Medical Biology, A*STAR, Biopolis, Singapore, 138648, Singapore. [email protected].
  • 61 National University of Singapore, Department of Paediatrics, Yong Loo Lin School of Medicine, Biopolis, Singapore, Singapore. [email protected].
  • 62 Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673, Singapore. [email protected].
  • 63 Medical Genetics Department, Koç University School of Medicine, 34010, Istanbul, Turkey. [email protected].
  • 64 Reproductive Biology Laboratory, Obstetrics and Gynaecology, Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ, Amsterdam-Zuidoost, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 32001716 DOI: 10.1038/s41467-020-14360-7
Abstract

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.

Figures