Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy PMID: 32001716

GLP-1 and Obesity Research

2026-08-18

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

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.

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.