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

• Published in: Nature communications Vol. 11; no. 1; p. 595
• Main Authors: Hengel, Holger, Bosso-Lefèvre, Célia, Grady, George, Szenker-Ravi, Emmanuelle, Li, Hankun, Pierce, Sarah, Lebigot, Élise, Tan, Thong-Teck, Eio, Michelle Y., Narayanan, Gunaseelan, Utami, Kagistia Hana, Yau, Monica, Handal, Nader, Deigendesch, Werner, Keimer, Reinhard, Marzouqa, Hiyam M., Gunay-Aygun, Meral, Muriello, Michael J., Verhelst, Helene, Weckhuysen, Sarah, Mahida, Sonal, Naidu, Sakkubai, Thomas, Terrence G., Lim, Jiin Ying, Tan, Ee Shien, Haye, Damien, Willemsen, Michèl A. A. P., Oegema, Renske, Mitchell, Wendy G., Pierson, Tyler Mark, Andrews, Marisa V., Willing, Marcia C., Rodan, Lance H., Barakat, Tahsin Stefan, van Slegtenhorst, Marjon, Gavrilova, Ralitza H., Martinelli, Diego, Gilboa, Tal, Tamim, Abdullah M., Hashem, Mais O., AlSayed, Moeenaldeen D., Abdulrahim, Maha M., Al-Owain, Mohammed, Awaji, Ali, Mahmoud, Adel A. H., Faqeih, Eissa A., Asmari, Ali Al, Algain, Sulwan M., Jad, Lamyaa A., Aldhalaan, Hesham M., Helbig, Ingo, Koolen, David A., Riess, Angelika, Kraegeloh-Mann, Ingeborg, Bauer, Peter, Gulsuner, Suleyman, Stamberger, Hannah, Ng, Alvin Yu Jin, Tang, Sha, Tohari, Sumanty, Keren, Boris, Schultz-Rogers, Laura E., Klee, Eric W., Barresi, Sabina, Tartaglia, Marco, Mor-Shaked, Hagar, Maddirevula, Sateesh, Begtrup, Amber, Telegrafi, Aida, Pfundt, Rolph, Schüle, Rebecca, Ciruna, Brian, Bonnard, Carine, Pouladi, Mahmoud A., Stewart, James C., Claridge-Chang, Adam, Lefeber, Dirk J., Alkuraya, Fowzan S., Mathuru, Ajay S., Venkatesh, Byrappa, Barycki, Joseph J., Simpson, Melanie A., Jamuar, Saumya S., Schöls, Ludger, Reversade, Bruno
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-01-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/51; 14/63; 45/88; 631/208/2489; 631/378/2571/1696; 631/45/221; 692/699/375/2609; 82/80; Adolescent; Alleles; Animals; Child; Child, Preschool; Dehydrogenase; Dehydrogenases; Delay; Encephalopathy; Enzymatic activity; Epilepsy; Epilepsy - genetics; Extracellular matrix; Female; Fibroblasts; Genes, Recessive; Glucose; Glycolipids; Humanities and Social Sciences; Humans; Hypotonia; Infant; Kinetics; Loss of Function Mutation - genetics; Male; multidisciplinary; Mutants; Mutation; Neural stem cells; Oligomerization; Organoids; Organoids - pathology; Oxidoreductase; Oxidoreductases - chemistry; Oxidoreductases - genetics; Pedigree; Protein Domains; Proteoglycans; Science; Science (multidisciplinary); Seizures; Stability; Syndrome; UDP-glucose 6-dehydrogenase; Uridine Diphosphate Glucose Dehydrogenase - genetics; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14360-7

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.
UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.