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 van 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; Bruno Reversade

doi:10.1038/s41467-020-14360-7

Back

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.11(1), pp.595-595

30/01/2020

DOI: https://doi.org/10.1038/s41467-020-14360-7

PMCID: PMC6992768

PMID: 32001716

Abstract

Adolescent

Alleles

Animals

Child

Child, Preschool

Epilepsy - genetics

Female

Genes, Recessive

Humans

Infant

Kinetics

Loss of Function Mutation - genetics

Male

Organoids - pathology

Oxidoreductases - chemistry

Oxidoreductases - genetics

Pedigree

Protein Domains

Syndrome

Uridine Diphosphate Glucose Dehydrogenase - genetics

Zebrafish

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.

Files and links (1)

url

https://doi.org/10.1038/s41467-020-14360-7View

Published (Version of record) Open

Metrics

1 Record Views

See more details

Details

Title: Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
Creators - without role: Holger Hengel - University of Tübingen
Célia Bosso-Lefèvre - Agency for Science, Technology and Research
George Grady - North Carolina State University
Emmanuelle Szenker-Ravi - Agency for Science, Technology and Research
Hankun Li - Yale-NUS College
Sarah Pierce - University of Washington
Élise Lebigot - Assistance Publique – Hôpitaux de Paris
Thong-Teck Tan - Agency for Science, Technology and Research
Michelle Y Eio - Agency for Science, Technology and Research
Gunaseelan Narayanan - Agency for Science, Technology and Research
Kagistia Hana Utami - Agency for Science, Technology and Research
Monica Yau - University of Toronto
Nader Handal - Little Company of Mary Hospital
Werner Deigendesch - Little Company of Mary Hospital
Reinhard Keimer - Ped Neurology, Staufer Hospital, Wetzgauer Straße 85, Schwäbisch-Gmünd, Germany
Hiyam M Marzouqa - Little Company of Mary Hospital
Meral Gunay-Aygun - Johns Hopkins Medicine
Michael J Muriello - Johns Hopkins University
Helene Verhelst - Ghent University Hospital
Sarah Weckhuysen - University of Antwerp
Sonal Mahida - Kennedy Krieger Institute
Sakkubai Naidu - Kennedy Krieger Institute
Terrence G Thomas - Boston Children's Hospital
Jiin Ying Lim - National University of Singapore
Ee Shien Tan - Duke-NUS Medical School
Damien Haye - Centre Hospitalier Universitaire de Nice
Michèl A A P Willemsen - Radboud University Nijmegen
Renske Oegema - Utrecht University
Wendy G Mitchell - University of Southern California
Tyler Mark Pierson - Cedars-Sinai Medical Center
Marisa V Andrews - Washington University in St. Louis
Marcia C Willing - Washington University in St. Louis
Lance H Rodan - Harvard University
Tahsin Stefan Barakat - Erasmus University Rotterdam
Marjon van Slegtenhorst - Erasmus University Rotterdam
Ralitza H Gavrilova - Mayo Clinic
Diego Martinelli - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, 00146, Rome, Italy
Tal Gilboa - Child Neurology Unit, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel
Abdullah M Tamim - Pediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Mais O Hashem - Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Moeenaldeen D AlSayed - Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Maha M Abdulrahim - Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Mohammed Al-Owain - Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Ali Awaji - King Fahad Central Hospital
Adel A H Mahmoud - National Neuroscience Institute
Eissa A Faqeih - Boston Children's Hospital
Ali Al Asmari - Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Sulwan M Algain - General Pediatrics and Adolescents, King Fahad Medical City, Riyadh, Saudi Arabia
Lamyaa A Jad - National Neuroscience Institute
Hesham M Aldhalaan - Neuroscience Department King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Ingo Helbig - University of Pennsylvania
David A Koolen - Radboud University Nijmegen
Angelika Riess - Centogene
Ingeborg Kraegeloh-Mann - University of Tübingen
Peter Bauer - Centogene
Suleyman Gulsuner - University of Washington
Hannah Stamberger - University of Antwerp
Alvin Yu Jin Ng - Institute of Molecular and Cell Biology, ASTAR, Biopolis, Singapore, 138673, Singapore
Sha Tang - Ambry Genetics
Sumanty Tohari - Agency for Science, Technology and Research
Boris Keren - Genomics
Laura E Schultz-Rogers - Mayo Clinic
Eric W Klee - Mayo Clinic
Sabina Barresi - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, 00146, Rome, Italy
Marco Tartaglia - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, 00146, Rome, Italy
Hagar Mor-Shaked - Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel
Sateesh Maddirevula - Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Amber Begtrup - GeneDx, 207 Perry Parkway, Gaithersburg, MD, 20877, USA
Aida Telegrafi - GeneDx, 207 Perry Parkway, Gaithersburg, MD, 20877, USA
Rolph Pfundt - Radboud University Nijmegen
Rebecca Schüle - University of Tübingen
Brian Ciruna - University of Toronto
Carine Bonnard - Agency for Science, Technology and Research
Mahmoud A Pouladi - Agency for Science, Technology and Research
James C Stewart - Institute of Molecular and Cell Biology, ASTAR, Biopolis, Singapore, 138673, Singapore
Adam Claridge-Chang - Agency for Science, Technology and Research
Dirk J Lefeber - Department of Laboratory Medicine, Translational Metabolic Laboratory, Nijmegen, The Netherlands
Fowzan S Alkuraya - Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Ajay S Mathuru - Agency for Science, Technology and Research
Byrappa Venkatesh - Agency for Science, Technology and Research
Joseph J Barycki - North Carolina State University
Melanie A Simpson - North Carolina State University
Saumya S Jamuar - Duke-NUS Medical School
Ludger Schöls - University of Tübingen
Bruno Reversade - Academic Medical Center
Publication Details: Nature communications, Vol.11(1), pp.595-595
Identifiers: 9915573008331
Academic Unit: Imam Abdulrahman Bin Faisal University; King Abdullah University of Science & Technology; King Faisal University; Alfaisal University
Language: English
Resource Type: Journal article