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

36 Scopus citations

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)
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14360-7
State	Published - Dec 1 2020
Externally published	Yes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-14360-7

Cite this

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). https://doi.org/10.1038/s41467-020-14360-7

@article{82d6cf442dd0464dad87cab3c6b82012,

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.",

author = "Holger Hengel and C{\'e}lia Bosso-Lef{\`e}vre and George Grady and Emmanuelle Szenker-Ravi and Hankun Li and Sarah Pierce and {\'E}lise Lebigot and Tan, {Thong Teck} and Eio, {Michelle Y.} and Gunaseelan Narayanan and Utami, {Kagistia Hana} and Monica Yau and Nader Handal and Werner Deigendesch and Reinhard Keimer and Marzouqa, {Hiyam M.} and Meral Gunay-Aygun and Muriello, {Michael J.} and Helene Verhelst and Sarah Weckhuysen and Sonal Mahida and Sakkubai Naidu and Thomas, {Terrence G.} and Lim, {Jiin Ying} and Tan, {Ee Shien} and Damien Haye and Willemsen, {Mich{\`e}l A.A.P.} and Renske Oegema and Mitchell, {Wendy G.} and Pierson, {Tyler Mark} and Andrews, {Marisa V.} and Willing, {Marcia C.} and Rodan, {Lance H.} and Barakat, {Tahsin Stefan} and {van Slegtenhorst}, Marjon and Gavrilova, {Ralitza H.} and Diego Martinelli and Tal Gilboa and Tamim, {Abdullah M.} and Hashem, {Mais O.} and AlSayed, {Moeenaldeen D.} and Abdulrahim, {Maha M.} and Mohammed Al-Owain and Ali Awaji and Mahmoud, {Adel A.H.} and Faqeih, {Eissa A.} and Asmari, {Ali Al} and Algain, {Sulwan M.} and Jad, {Lamyaa A.} and Aldhalaan, {Hesham M.} and Ingo Helbig and Koolen, {David A.} and Angelika Riess and Ingeborg Kraegeloh-Mann and Peter Bauer and Suleyman Gulsuner and Hannah Stamberger and Ng, {Alvin Yu Jin} and Sha Tang and Sumanty Tohari and Boris Keren and Schultz-Rogers, {Laura E.} and Klee, {Eric W.} and Sabina Barresi and Marco Tartaglia and Hagar Mor-Shaked and Sateesh Maddirevula and Amber Begtrup and Aida Telegrafi and Rolph Pfundt and Rebecca Sch{\"u}le and Brian Ciruna and Carine Bonnard and Pouladi, {Mahmoud A.} and Stewart, {James C.} and Adam Claridge-Chang and Lefeber, {Dirk J.} and Alkuraya, {Fowzan S.} and Mathuru, {Ajay S.} and Byrappa Venkatesh and Barycki, {Joseph J.} and Simpson, {Melanie A.} and Jamuar, {Saumya S.} and Ludger Sch{\"o}ls and Bruno Reversade",

note = "Generated from Scopus record by KAUST IRTS on 2023-02-15",

year = "2020",

month = dec,

day = "1",

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

language = "English (US)",

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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. https://doi.org/10.1038/s41467-020-14360-7

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

N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15

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.

UR - https://www.nature.com/articles/s41467-020-14360-7

UR - http://www.scopus.com/inward/record.url?scp=85078711726&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14360-7

DO - 10.1038/s41467-020-14360-7

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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