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

doi:10.1038/s41467-020-14360-7

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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	595
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14360-7
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Hengel, H., Bosso-Lefèvre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, É., Tan, T. T., Eio, M. Y., Narayanan, G., Utami, K. H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H. M., Gunay-Aygun, M., Muriello, M. J., Verhelst, H., ... Reversade, B. (2020). Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nature communications, 11(1), Article 595. https://doi.org/10.1038/s41467-020-14360-7

Hengel, H, Bosso-Lefèvre, C, Grady, G, Szenker-Ravi, E, Li, H, Pierce, S, Lebigot, É, Tan, TT, Eio, MY, Narayanan, G, Utami, KH, Yau, M, Handal, N, Deigendesch, W, Keimer, R, Marzouqa, HM, Gunay-Aygun, M, Muriello, MJ, Verhelst, H, Weckhuysen, S, Mahida, S, Naidu, S, Thomas, TG, Lim, JY, Tan, ES, Haye, D, Willemsen, MAAP, Oegema, R, Mitchell, WG, Pierson, TM, Andrews, MV, Willing, MC, Rodan, LH, Barakat, TS, van Slegtenhorst, M, Gavrilova, RH, Martinelli, D, Gilboa, T, Tamim, AM, Hashem, MO, AlSayed, MD, Abdulrahim, MM, Al-Owain, M, Awaji, A, Mahmoud, AAH, Faqeih, EA, Asmari, AA, Algain, SM, Jad, LA, Aldhalaan, HM, Helbig, I, Koolen, DA, Riess, A, Kraegeloh-Mann, I, Bauer, P, Gulsuner, S, Stamberger, H, Ng, AYJ, Tang, S, Tohari, S, Keren, B, Schultz-Rogers, LE, Klee, EW, Barresi, S, Tartaglia, M, Mor-Shaked, H, Maddirevula, S, Begtrup, A, Telegrafi, A, Pfundt, R, Schüle, R, Ciruna, B, Bonnard, C, Pouladi, MA, Stewart, JC, Claridge-Chang, A, Lefeber, DJ, Alkuraya, FS, Mathuru, AS, Venkatesh, B, Barycki, JJ, Simpson, MA, Jamuar, SS, Schöls, L & Reversade, B 2020, 'Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy', Nature communications, vol. 11, no. 1, 595. https://doi.org/10.1038/s41467-020-14360-7

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title = "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{\textquoteright} 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.",

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doi = "10.1038/s41467-020-14360-7",

language = "English (US)",

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TY - JOUR

T1 - Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AU - Hengel, Holger

AU - Bosso-Lefèvre, Célia

AU - Grady, George

AU - Szenker-Ravi, Emmanuelle

AU - Li, Hankun

AU - Pierce, Sarah

AU - Lebigot, Élise

AU - Tan, Thong Teck

AU - Eio, Michelle Y.

AU - Narayanan, Gunaseelan

AU - Utami, Kagistia Hana

AU - Yau, Monica

AU - Handal, Nader

AU - Deigendesch, Werner

AU - Keimer, Reinhard

AU - Marzouqa, Hiyam M.

AU - Gunay-Aygun, Meral

AU - Muriello, Michael J.

AU - Verhelst, Helene

AU - Weckhuysen, Sarah

AU - Mahida, Sonal

AU - Naidu, Sakkubai

AU - Thomas, Terrence G.

AU - Lim, Jiin Ying

AU - Tan, Ee Shien

AU - Haye, Damien

AU - Willemsen, Michèl A.A.P.

AU - Oegema, Renske

AU - Mitchell, Wendy G.

AU - Pierson, Tyler Mark

AU - Andrews, Marisa V.

AU - Willing, Marcia C.

AU - Rodan, Lance H.

AU - Barakat, Tahsin Stefan

AU - van Slegtenhorst, Marjon

AU - Gavrilova, Ralitza H.

AU - Martinelli, Diego

AU - Gilboa, Tal

AU - Tamim, Abdullah M.

AU - Hashem, Mais O.

AU - AlSayed, Moeenaldeen D.

AU - Abdulrahim, Maha M.

AU - Al-Owain, Mohammed

AU - Awaji, Ali

AU - Mahmoud, Adel A.H.

AU - Faqeih, Eissa A.

AU - Asmari, Ali Al

AU - Algain, Sulwan M.

AU - Jad, Lamyaa A.

AU - Aldhalaan, Hesham M.

AU - Helbig, Ingo

AU - Koolen, David A.

AU - Riess, Angelika

AU - Kraegeloh-Mann, Ingeborg

AU - Bauer, Peter

AU - Gulsuner, Suleyman

AU - Stamberger, Hannah

AU - Ng, Alvin Yu Jin

AU - Tang, Sha

AU - Tohari, Sumanty

AU - Keren, Boris

AU - Schultz-Rogers, Laura E.

AU - Klee, Eric W.

AU - Barresi, Sabina

AU - Tartaglia, Marco

AU - Mor-Shaked, Hagar

AU - Maddirevula, Sateesh

AU - Begtrup, Amber

AU - Telegrafi, Aida

AU - Pfundt, Rolph

AU - Schüle, Rebecca

AU - Ciruna, Brian

AU - Bonnard, Carine

AU - Pouladi, Mahmoud A.

AU - Stewart, James C.

AU - Claridge-Chang, Adam

AU - Lefeber, Dirk J.

AU - Alkuraya, Fowzan S.

AU - Mathuru, Ajay S.

AU - Venkatesh, Byrappa

AU - Barycki, Joseph J.

AU - Simpson, Melanie A.

AU - Jamuar, Saumya S.

AU - Schöls, Ludger

AU - Reversade, Bruno

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-14360-7

DO - 10.1038/s41467-020-14360-7

M3 - Article

C2 - 32001716

AN - SCOPUS:85078711726

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 595

ER -

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

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