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

Author

Listed:
  • Holger Hengel

    (University of Tübingen
    German Center of Neurodegenerative Diseases (DZNE))

  • Célia Bosso-Lefèvre

    (Institute of Medical Biology, A*STAR, Biopolis
    Yong Loo Lin School of Medicine, Biopolis)

  • George Grady

    (Department of Molecular and Structural Biochemistry North Carolina State University)

  • Emmanuelle Szenker-Ravi

    (Institute of Medical Biology, A*STAR, Biopolis)

  • Hankun Li

    (Yale-NUS College, 12 College Avenue West, Biopolis)

  • Sarah Pierce

    (University of Washington)

  • Élise Lebigot

    (Hopital Bicêtre, Assistance publique-Hôpitaux de Paris, 78 avenue du general leclerc)

  • Thong-Teck Tan

    (Singapore Stem Cell Bank, A∗STAR, Biopolis)

  • Michelle Y. Eio

    (Singapore Stem Cell Bank, A∗STAR, Biopolis)

  • Gunaseelan Narayanan

    (Singapore Stem Cell Bank, A∗STAR, Biopolis)

  • Kagistia Hana Utami

    (Technology, and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5)

  • Monica Yau

    (The University of Toronto)

  • Nader Handal

    (Caritas Baby Hospital Bethlehem)

  • Werner Deigendesch

    (Caritas Baby Hospital Bethlehem)

  • Reinhard Keimer

    (Ped Neurology, Staufer Hospital)

  • Hiyam M. Marzouqa

    (Caritas Baby Hospital Bethlehem)

  • Meral Gunay-Aygun

    (Johns Hopkins University School of Medicine)

  • Michael J. Muriello

    (Johns Hopkins University School of Medicine)

  • Helene Verhelst

    (Ghent University Hospital)

  • Sarah Weckhuysen

    (Center for Molecular Neurology, VIB
    University of Antwerp
    University Hospital Antwerp)

  • Sonal Mahida

    (Kennedy Krieger Institute)

  • Sakkubai Naidu

    (Kennedy Krieger Institute)

  • Terrence G. Thomas

    (KK Women’s and Children’s Hospital)

  • Jiin Ying Lim

    (KK Women’s and Children’s Hospital
    Duke-NUS Medical School
    SingHealth Duke-NUS Genomic Medicine Centre)

  • Ee Shien Tan

    (KK Women’s and Children’s Hospital
    Duke-NUS Medical School
    SingHealth Duke-NUS Genomic Medicine Centre)

  • Damien Haye

    (CHU De Nice Hôpital de l’Archet 2, 151 route Saint Antoine de la Ginestière, CS 23079 062002)

  • Michèl A. A. P. Willemsen

    (Radboud University Medical Center)

  • Renske Oegema

    (University Medical Center Utrecht)

  • Wendy G. Mitchell

    (Keck School of Medicine of University of Southern California)

  • Tyler Mark Pierson

    (Cedars-Sinai Medical Center)

  • Marisa V. Andrews

    (Washington University School of Medicine)

  • Marcia C. Willing

    (Washington University School of Medicine)

  • Lance H. Rodan

    (Boston Children’s Hospital)

  • Tahsin Stefan Barakat

    (University Medical Center, Wytemaweg 80)

  • Marjon Slegtenhorst

    (University Medical Center, Wytemaweg 80)

  • Ralitza H. Gavrilova

    (Mayo Clinic)

  • Diego Martinelli

    (Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15)

  • Tal Gilboa

    (Hadassah-Hebrew University Medical Center)

  • Abdullah M. Tamim

    (King Faisal Specialist Hospital and Research Center)

  • Mais O. Hashem

    (King Faisal Specialist Hospital and Research Center)

  • Moeenaldeen D. AlSayed

    (King Faisal Specialist Hospital and Research Center)

  • Maha M. Abdulrahim

    (King Faisal Specialist Hospital and Research Center)

  • Mohammed Al-Owain

    (King Faisal Specialist Hospital and Research Center)

  • Ali Awaji

    (King Fahad Central Hospital in Jizan)

  • Adel A. H. Mahmoud

    (King Fahad Medical City)

  • Eissa A. Faqeih

    (Children’s Hospital, King Fahad Medical City)

  • Ali Al Asmari

    (Children’s Hospital, King Fahad Medical City)

  • Sulwan M. Algain

    (King Fahad Medical City)

  • Lamyaa A. Jad

    (King Fahad Medical City)

  • Hesham M. Aldhalaan

    (Neuroscience Department King Faisal Specialist Hospital and Research Center)

  • Ingo Helbig

    (The Children’s Hospital of Philadelphia)

  • David A. Koolen

    (Radboud University Medical Center)

  • Angelika Riess

    (Institute of Medical Genetics and Applied Genomics (Tübingen) and Centogene AG (Rostock))

  • Ingeborg Kraegeloh-Mann

    (University of Tübingen)

  • Peter Bauer

    (Institute of Medical Genetics and Applied Genomics (Tübingen) and Centogene AG (Rostock))

  • Suleyman Gulsuner

    (University of Washington)

  • Hannah Stamberger

    (Center for Molecular Neurology, VIB
    University of Antwerp
    University Hospital Antwerp)

  • Alvin Yu Jin Ng

    (A*STAR, Biopolis)

  • Sha Tang

    (Division of Clinical Genomics, Ambry Genetics)

  • Sumanty Tohari

    (A*STAR, Biopolis)

  • Boris Keren

    (APHP, GH Pitié Salpêtrière, Department of Genetics, Unit of Development Genomics)

  • Laura E. Schultz-Rogers

    (Mayo Clinic)

  • Eric W. Klee

    (Mayo Clinic)

  • Sabina Barresi

    (Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15)

  • Marco Tartaglia

    (Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15)

  • Hagar Mor-Shaked

    (Hadassah-Hebrew University Medical Center)

  • Sateesh Maddirevula

    (King Faisal Specialist Hospital and Research Center)

  • Amber Begtrup

    (GeneDx, 207 Perry Parkway)

  • Aida Telegrafi

    (GeneDx, 207 Perry Parkway)

  • Rolph Pfundt

    (Radboud University Medical Center)

  • Rebecca Schüle

    (University of Tübingen
    German Center of Neurodegenerative Diseases (DZNE))

  • Brian Ciruna

    (The University of Toronto)

  • Carine Bonnard

    (Institute of Medical Biology, A*STAR, Biopolis)

  • Mahmoud A. Pouladi

    (Technology, and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5
    National University of Singapore
    National University of Singapore)

  • James C. Stewart

    (A*STAR, Biopolis)

  • Adam Claridge-Chang

    (A*STAR, Biopolis
    Duke-NUS Medical School)

  • Dirk J. Lefeber

    (Donders Center for Brain, Cognition, and Behavior
    Translational Metabolic Laboratory)

  • Fowzan S. Alkuraya

    (King Faisal Specialist Hospital and Research Center)

  • Ajay S. Mathuru

    (Yale-NUS College, 12 College Avenue West, Biopolis
    A*STAR, Biopolis)

  • Byrappa Venkatesh

    (Yong Loo Lin School of Medicine, Biopolis
    A*STAR, Biopolis)

  • Joseph J. Barycki

    (Department of Molecular and Structural Biochemistry North Carolina State University)

  • Melanie A. Simpson

    (Department of Molecular and Structural Biochemistry North Carolina State University)

  • Saumya S. Jamuar

    (KK Women’s and Children’s Hospital
    Duke-NUS Medical School
    SingHealth Duke-NUS Genomic Medicine Centre
    SingHealth Duke-NUS Institute of Precision Medicine)

  • Ludger Schöls

    (University of Tübingen
    German Center of Neurodegenerative Diseases (DZNE))

  • Bruno Reversade

    (Institute of Medical Biology, A*STAR, Biopolis
    Yong Loo Lin School of Medicine, Biopolis
    A*STAR, Biopolis
    Koç University School of Medicine)

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.

Suggested Citation

  • Holger Hengel & Célia Bosso-Lefèvre & George Grady & Emmanuelle Szenker-Ravi & Hankun Li & Sarah Pierce & Élise Lebigot & Thong-Teck Tan & Michelle Y. Eio & Gunaseelan Narayanan & Kagistia Hana Utami , 2020. "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14360-7
    DOI: 10.1038/s41467-020-14360-7
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    Cited by:

    1. Tao Zhang & Na Zhang & Jing Xing & Shuhua Zhang & Yulu Chen & Daichao Xu & Jinyang Gu, 2023. "UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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