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

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.

SUBMITTER: Hengel H 

PROVIDER: S-EPMC6992768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Hengel Holger H   Bosso-Lefèvre Célia C   Grady George G   Szenker-Ravi Emmanuelle E   Li Hankun H   Pierce Sarah S   Lebigot Élise É   Tan Thong-Teck TT   Eio Michelle Y MY   Narayanan Gunaseelan G   Utami Kagistia Hana KH   Yau Monica M   Handal Nader N   Deigendesch Werner W   Keimer Reinhard R   Marzouqa Hiyam M HM   Gunay-Aygun Meral M   Muriello Michael J MJ   Verhelst Helene H   Weckhuysen Sarah S   Mahida Sonal S   Naidu Sakkubai S   Thomas Terrence G TG   Lim Jiin Ying JY   Tan Ee Shien ES   Haye Damien D   Willemsen Michèl A A P MAAP   Oegema Renske R   Mitchell Wendy G WG   Pierson Tyler Mark TM   Andrews Marisa V MV   Willing Marcia C MC   Rodan Lance H LH   Barakat Tahsin Stefan TS   van Slegtenhorst Marjon M   Gavrilova Ralitza H RH   Martinelli Diego D   Gilboa Tal T   Tamim Abdullah M AM   Hashem Mais O MO   AlSayed Moeenaldeen D MD   Abdulrahim Maha M MM   Al-Owain Mohammed M   Awaji Ali A   Mahmoud Adel A H AAH   Faqeih Eissa A EA   Asmari Ali Al AA   Algain Sulwan M SM   Jad Lamyaa A LA   Aldhalaan Hesham M HM   Helbig Ingo I   Koolen David A DA   Riess Angelika A   Kraegeloh-Mann Ingeborg I   Bauer Peter P   Gulsuner Suleyman S   Stamberger Hannah H   Ng Alvin Yu Jin AYJ   Tang Sha S   Tohari Sumanty S   Keren Boris B   Schultz-Rogers Laura E LE   Klee Eric W EW   Barresi Sabina S   Tartaglia Marco M   Mor-Shaked Hagar H   Maddirevula Sateesh S   Begtrup Amber A   Telegrafi Aida A   Pfundt Rolph R   Schüle Rebecca R   Ciruna Brian B   Bonnard Carine C   Pouladi Mahmoud A MA   Stewart James C JC   Claridge-Chang Adam A   Lefeber Dirk J DJ   Alkuraya Fowzan S FS   Mathuru Ajay S AS   Venkatesh Byrappa B   Barycki Joseph J JJ   Simpson Melanie A MA   Jamuar Saumya S SS   Schöls Ludger L   Reversade Bruno B  

Nature communications 20200130 1

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-functi  ...[more]

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