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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; [...]

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

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  • Media type: E-Article
  • Title: Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
  • Contributor: 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; [...]
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-020-14360-7
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>UGDH</jats:italic> in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. <jats:italic>UGDH</jats:italic> 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 <jats:italic>ugdh</jats:italic> 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, <jats:italic>UGDH</jats:italic> mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p>
  • Access State: Open Access