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

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, Monica Yau, Nader Handal, Werner Deigendesch, Reinhard Keimer, Hiyam M. Marzouqa, Meral Gunay-Aygun, Michael J. Muriello, Helene Verhelst, Sarah Weckhuysen, Sonal Mahida, Sakkubai Naidu, Terrence G. Thomas, Jiin Ying Lim, Ee Shien Tan, Damien Haye, Michèl A. A. P. Willemsen, Renske Oegema, Wendy G. Mitchell, Tyler Mark Pierson, Marisa V. Andrews, Marcia C. Willing, Lance H. Rodan, Tahsin Stefan Barakat, Marjon Slegtenhorst, Ralitza H. Gavrilova, Diego Martinelli, Tal Gilboa, Abdullah M. Tamim, Mais O. Hashem, Moeenaldeen D. AlSayed, Maha M. Abdulrahim, Mohammed Al-Owain, Ali Awaji, Adel A. H. Mahmoud, Eissa A. Faqeih, Ali Al Asmari, Sulwan M. Algain, Lamyaa A. Jad, Hesham M. Aldhalaan, Ingo Helbig, David A. Koolen, Angelika Riess, Ingeborg Kraegeloh-Mann, Peter Bauer, Suleyman Gulsuner, Hannah Stamberger, Alvin Yu Jin Ng, Sha Tang, Sumanty Tohari, Boris Keren, Laura E. Schultz-Rogers, Eric W. Klee, Sabina Barresi, Marco Tartaglia, Hagar Mor-Shaked, Sateesh Maddirevula, Amber Begtrup, Aida Telegrafi, Rolph Pfundt, Rebecca Schüle, Brian Ciruna, Carine Bonnard, Mahmoud A. Pouladi, James C. Stewart, Adam Claridge-Chang, Dirk J. Lefeber, Fowzan S. Alkuraya, Ajay S. Mathuru, Byrappa Venkatesh, Joseph J. Barycki, Melanie A. Simpson, Saumya S. Jamuar, Ludger Schöls () and Bruno Reversade ()
Additional contact information
Holger Hengel: University of Tübingen
Célia Bosso-Lefèvre: Institute of Medical Biology, A*STAR, 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
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
Ee Shien Tan: KK Women’s and Children’s Hospital
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
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
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
James C. Stewart: A*STAR, Biopolis
Adam Claridge-Chang: A*STAR, Biopolis
Dirk J. Lefeber: Donders Center for Brain, Cognition, and Behavior
Fowzan S. Alkuraya: King Faisal Specialist Hospital and Research Center
Ajay S. Mathuru: Yale-NUS College, 12 College Avenue West, Biopolis
Byrappa Venkatesh: Yong Loo Lin School of Medicine, 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
Ludger Schöls: University of Tübingen
Bruno Reversade: Institute of Medical Biology, A*STAR, Biopolis

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14360-7

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