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5 results on '"Schultz-Rogers, L.E."'

1. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., Tartaglia, M., Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., and Tartaglia, M.

Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access), Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

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

Author

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

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.

Published
2020
Full Text
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3. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Author

Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., 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., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., Reversade, B., Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., 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., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., and Reversade, B.

Abstract

Contains fulltext : 218288.pdf (publisher's version ) (Open Access), 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.

Published
2020

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

Author

Reversade, Bruno, 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.; Weckhuysen, S.; Mahida, S.; Naidu, S.; Thomas, T.G.; Lim, J.Y.; Tan, E.S.; Haye, D.; Willemsen, M.A.A.P.; Oegema, R.; Mitchell, W.G.; Pierson, T.M.; Andrews, M.V.; Willing, M.C.; Rodan, L.H.; Barakat, T.S.; van Slegtenhorst, M.; Gavrilova, R.H.; Martinelli, D.; Gilboa, T.; Tamim, A.M.; Hashem, M.O.; AlSayed, M.D.; Abdulrahim, M.M.; Al-Owain, M.; Awaji, A.; Mahmoud, A.A.H.; Faqeih, E.A.; Asmari, A.A.; Algain, S.M.; Jad, L.A.; Aldhalaan, H.M.; Helbig, I.; Koolen, D.A.; Riess, A.; Kraegeloh-Mann, I.; Bauer, P.; Gulsuner, S.; Stamberger, H.; Ng, A.Y.J.; Tang, S.; Tohari, S.; Keren, B.; Schultz-Rogers, L.E.; Klee, E.W.; Barresi, S.; Tartaglia, M.; Mor-Shaked, H.; Maddirevula, S.; Begtrup, A.; Telegrafi, A.; Pfundt, R.; Schüle, R.; Ciruna, B.; Bonnard, C.; Pouladi, M.A.; Stewart, J.C.; Claridge-Chang, A.; Lefeber, D.J.; Alkuraya, F.S.; Mathuru, A.S.; Venkatesh, B.; Barycki, J.J.; Simpson, M.A.; Jamuar, S.S.; Schöls, L, School of Medicine, Reversade, Bruno, 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.; Weckhuysen, S.; Mahida, S.; Naidu, S.; Thomas, T.G.; Lim, J.Y.; Tan, E.S.; Haye, D.; Willemsen, M.A.A.P.; Oegema, R.; Mitchell, W.G.; Pierson, T.M.; Andrews, M.V.; Willing, M.C.; Rodan, L.H.; Barakat, T.S.; van Slegtenhorst, M.; Gavrilova, R.H.; Martinelli, D.; Gilboa, T.; Tamim, A.M.; Hashem, M.O.; AlSayed, M.D.; Abdulrahim, M.M.; Al-Owain, M.; Awaji, A.; Mahmoud, A.A.H.; Faqeih, E.A.; Asmari, A.A.; Algain, S.M.; Jad, L.A.; Aldhalaan, H.M.; Helbig, I.; Koolen, D.A.; Riess, A.; Kraegeloh-Mann, I.; Bauer, P.; Gulsuner, S.; Stamberger, H.; Ng, A.Y.J.; Tang, S.; Tohari, S.; Keren, B.; Schultz-Rogers, L.E.; Klee, E.W.; Barresi, S.; Tartaglia, M.; Mor-Shaked, H.; Maddirevula, S.; Begtrup, A.; Telegrafi, A.; Pfundt, R.; Schüle, R.; Ciruna, B.; Bonnard, C.; Pouladi, M.A.; Stewart, J.C.; Claridge-Chang, A.; Lefeber, D.J.; Alkuraya, F.S.; Mathuru, A.S.; Venkatesh, B.; Barycki, J.J.; Simpson, M.A.; Jamuar, S.S.; Schöls, L, and School of Medicine

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., German Research Foundation (DFG); European Union (European Union); NEUROMICS Network; International Coordination Action (ICA); Fund for Scientific Research Flanders (FWO); Netherlands Organization for Scientific Research (ZONMW VIDI); National Medical Research Council, Singapore; A Strategic Positioning Fund on Genetic Orphan Diseases (GODAFIT); Industry Alignment Fund on Singapore Childhood Undiagnosed Diseases Program (SUREKids); Biomedical Research Council, A*STAR; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases; Fondazione Bambino Gesù (Vite Coraggiose); Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Eurocores Program EuroEPINOMICS; University of Antwerp Research Fund; FRAXA Foundation; Brain & Behavior Research Foundation, NARSAD Young Investigator Grant

Published
2020

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

Author

Ali Al Asmari, Emmanuelle Szenker-Ravi, Carine Bonnard, Bruno Reversade, Laura Schultz-Rogers, I. Kraegeloh-Mann, Maha Abdulrahim, Hesham Aldhalaan, Byrappa Venkatesh, Célia Bosso-Lefèvre, Aida Telegrafi, Hiyam M. Marzouqa, Gunaseelan Narayanan, Sha Tang, Sonal Mahida, Melanie A. Simpson, Fowzan S. Alkuraya, Michelle Eio, Eissa Faqeih, Renske Oegema, Sarah Weckhuysen, George Grady, Joseph J. Barycki, Mohammed Al-Owain, Lamyaa A. Jad, David A. Koolen, Marjon van Slegtenhorst, Tyler Mark Pierson, Marisa V. Andrews, Rebecca Schüle, Reinhard Keimer, Amber Begtrup, Sateesh Maddirevula, Michael Muriello, Sakkubai Naidu, Damien Haye, Adel A H Mahmoud, Brian Ciruna, Abdullah Tamim, Thong Teck Tan, Rolph Pfundt, Peter Bauer, Jiin Ying Lim, Ali Awaji, Marco Tartaglia, Meral Gunay-Aygun, Eric W. Klee, Marcia C. Willing, Monica Yau, Angelika Riess, Diego Martinelli, Sabina Barresi, Sumanty Tohari, Werner Deigendesch, Dirk Lefeber, Saumya Shekhar Jamuar, Ludger Schöls, Ralitza H. Gavrilova, Alvin Yu Jin Ng, Hannah Stamberger, Suleyman Gulsuner, Adam Claridge-Chang, Élise Lebigot, Moeenaldeen Al-Sayed, Ee Shien Tan, Kagistia Hana Utami, Sarah B. Pierce, Helene Verhelst, Hankun Li, James C. Stewart, Ingo Helbig, Tal Gilboa, Mahmoud A. Pouladi, Hagar Mor-Shaked, Boris Keren, Ajay S. Mathuru, Holger Hengel, Michèl A.A.P. Willemsen, Nader Handal, Tahsin Stefan Barakat, Sulwan M. Algain, Terrence Thomas, Lance H. Rodan, Mais Hashem, Wendy G. Mitchell, Center for Reproductive Medicine, ARD - Amsterdam Reproduction and Development, ACS - Diabetes & metabolism, Clinical Genetics, Reversade, Bruno, 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., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., van Slegtenhorst, M., Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y.J., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R., Schüle, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, M.A., Jamuar, S.S., Schöls, L, and School of Medicine

Subjects
0301 basic medicine, Male, Glycobiology, General Physics and Astronomy, VARIANTS, Encephalopathy, Neurodegenerative, Germline, 0302 clinical medicine, UDP-GLUCOSE DEHYDROGENASE, Loss of Function Mutation, Medicine and Health Sciences, EMBRYOGENESIS, 2.1 Biological and endogenous factors, UGDH protein, human, Aetiology, Child, lcsh:Science, Zebrafish, UTILITY, Genetics, pathology [Organoids], Multidisciplinary, Uridine diphosphate glucose dehydrogenase, Uridine diphosphate, DP-glucuronic acid, Syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Pedigree, DEFICIENCY, genetics [Loss of Function Mutation], Organoids, genetics [Uridine Diphosphate Glucose Dehydrogenase], Child, Preschool, Neurological, Medicine, Female, ddc:500, medicine.symptom, Oxidoreductases, Engineering sciences. Technology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], ENZYME, Adolescent, CONGENITAL DISORDER, Science, Intellectual and Developmental Disabilities (IDD), genetics [Epilepsy], chemistry [Oxidoreductases], Genetics and Molecular Biology, Genes, Recessive, Biology, Uridine Diphosphate Glucose Dehydrogenase, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Protein Domains, medicine, Animals, Humans, Recessive, Clinical genetics, Allele, Preschool, Gene, Loss function, Alleles, HEPARAN-SULFATE, Phenocopy, genetics [Oxidoreductases], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Epilepsy, GLYCOSYLATION, Neurosciences, Infant, General Chemistry, biology.organism_classification, medicine.disease, Brain Disorders, carbohydrates (lipids), Kinetics, 030104 developmental biology, Genes, General Biochemistry, Neuronal development, lcsh:Q, Human medicine, 030217 neurology & neurosurgery, Congenital disorder
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., German Research Foundation (DFG); European Union (European Union); NEUROMICS Network; International Coordination Action (ICA); Fund for Scientific Research Flanders (FWO); Netherlands Organization for Scientific Research (ZONMW VIDI); National Medical Research Council, Singapore; A Strategic Positioning Fund on Genetic Orphan Diseases (GODAFIT); Industry Alignment Fund on Singapore Childhood Undiagnosed Diseases Program (SUREKids); Biomedical Research Council, A*STAR; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases; Fondazione Bambino Gesù (Vite Coraggiose); Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Eurocores Program EuroEPINOMICS; University of Antwerp Research Fund; FRAXA Foundation; Brain & Behavior Research Foundation, NARSAD Young Investigator Grant

Published
2020
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