Hengel, H., Bosso-Lefèvre, C., Grady, G. et al. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun 11, 595 (2020). https://doi.org/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.
This study has been supported by the German Research Foundation (DFG, grant SCHO754/5-2 to L.S. and H.M.M.), by the European Union through funding for the NEUROMICS network (F5-2012-305121 to L.S.), by A Strategic Positioning Fund on Genetic Orphan Diseases (GODAFIT) and an Industry Alignment Fund on Singapore Childhood Undiagnosed Diseases Program (SUREKids) from the Biomedical Research Council, A*STAR, Singapore. T.M.P. was supported by the Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. M.T. was supported by the Fondazione Bambino Gesù (Vite Coraggiose) whose study was in the frame of the ongoing “Undiagnosed Patients Program”, Ospedale Pediatrico Bambino Gesù, Rome. B.C. is supported by operating grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. S.W. is supported by the Eurocores program EuroEPINOMICS, the Fund for Scientific Research Flanders (FWO), the International Coordination Action (ICA) grant G0E8614N, and the University of Antwerp (research fund). H.S. is a Ph.D fellow of the Fund for Scientific Research Flanders (1125416 N). D.J.L. received financial support obtained from the Netherlands Organization for Scientific Research (ZONMW VIDI grant 91713359 to D.J.L.). S.S.J. is supported by National Medical Research Council, Singapore (NMRC/CISSP/0003/2016). B.R. is a fellow of the Branco Weiss Foundation, an A*STAR Investigator, a Young EMBO Investigator, a Senior NRF and AAA fellow. K.H.U was supported by the FRAXA Foundation. Furthermore, we would like to thank the EuroEPINOMICS-RES NLES Working Group for their support by screening their database and matching Family 3. T.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021) and by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation.