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 B. Pierce, Élise Lebigot, Thong-Teck Tan, Michelle Eio, Gunaseelan Narayanan, Kagistia Hana Utami, Monica Yau, Nader Handal, Werner Deigendesch, Reinhard Keimer, Hiyam Marzouqa, Meral Gunay‐Aygun, Michael Muriello, Hélène Verhelst, Sarah Weckhuysen, Sonal Mahida, Sakkubai Naidu, Terrence 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 Willing, Lance H. Rodan, Tahsin Stefan Barakat, Marjon van Slegtenhorst, Ralitza H. Gavrilova, Diego Martinelli, Tal Gilboa, Abdullah Tamim, Mais O. Hashem, Moeenaldeen AlSayed, Maha Abdulrahim, Mohammed Al‐Owain, Ali Awaji, Adel Mahmoud, Eissa Faqeih, Ali Al Asmari, Sulwan Algain, Lamyaa Jad, Hesham Aldhalaan, Ingo Helbig, David A. Koolen, Angelika Rieß, Ingeborg Kraegeloh‐Mann, Peter Bauer, Süleyman Gülsüner, Hannah Stamberger, Alvin Yu Jin Ng, Sha Tang, Sumanty Tohari, Boris Keren, Laura 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 Stewart, Adam Claridge‐Chang, Dirk J. Lefeber, Fowzan S. Alkuraya, Ajay S. Mathuru, Byrappa Venkatesh, Joseph Barycki, Melanie A. Simpson, Saumya Shekhar Jamuar, Lüdger Schöls, Bruno Reversade
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.