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

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      1 , 2 , 3 , 4 , 5 , 3 , 6 , 7 , 8 , 9 , 9 , 9 , 10 , 11 , 12 , 12 , 13 , 12 , 14 , 14 , 15 , 16 , 17 , 18 , 19 , 19 , 20 , 21 , 22 , 23 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 29 , 30 , 31 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 37 , 37 , 38 , 39 , 40 , 40 , 41 , 39 , 42 , 43 , 44 , 45 , 46 , 45 , 7 , 16 , 17 , 18 , 47 , 48 , 47 , 49 , 32 , 32 , 33 , 33 , 50 , 36 , 51 , 51 , 44 , 1 , 2 , 11 , 3 , 10 , 52 , 53 , 47 , 47 , 54 , 55 , 56 , 36 , 6 , 47 , 4 , 47 , 5 , 5 , 21 , 22 , 23 , 57 , 1 , 2 , , 3 , 4 , 47 , 58 , 59 ,
      Nature Communications
      Nature Publishing Group UK
      Glycobiology, Clinical genetics, Neuronal development, Encephalopathy

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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.

          Abstract

          UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.

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          Most cited references39

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          InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

          In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.
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            Human Splicing Finder: an online bioinformatics tool to predict splicing signals

            Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effects of mutations on splicing signals or to identify splicing motifs in any human sequence. It contains all available matrices for auxiliary sequence prediction as well as new ones for binding sites of the 9G8 and Tra2-β Serine-Arginine proteins and the hnRNP A1 ribonucleoprotein. We also developed new Position Weight Matrices to assess the strength of 5′ and 3′ splice sites and branch points. We evaluated HSF efficiency using a set of 83 intronic and 35 exonic mutations known to result in splicing defects. We showed that the mutation effect was correctly predicted in almost all cases. HSF could thus represent a valuable resource for research, diagnostic and therapeutic (e.g. therapeutic exon skipping) purposes as well as for global studies, such as the GEN2PHEN European Project or the Human Variome Project.
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              DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach

              Cancer genome and other sequencing initiatives are generating extensive data on non-synonymous single nucleotide polymorphisms (nsSNPs) in human and other genomes. In order to understand the impacts of nsSNPs on the structure and function of the proteome, as well as to guide protein engineering, accurate in silicomethodologies are required to study and predict their effects on protein stability. Despite the diversity of available computational methods in the literature, none has proven accurate and dependable on its own under all scenarios where mutation analysis is required. Here we present DUET, a web server for an integrated computational approach to study missense mutations in proteins. DUET consolidates two complementary approaches (mCSM and SDM) in a consensus prediction, obtained by combining the results of the separate methods in an optimized predictor using Support Vector Machines (SVM). We demonstrate that the proposed method improves overall accuracy of the predictions in comparison with either method individually and performs as well as or better than similar methods. The DUET web server is freely and openly available at http://structure.bioc.cam.ac.uk/duet.
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                Author and article information

                Contributors
                ludger.schoels@uni-tuebingen.de
                bruno@reversade.com
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                30 January 2020
                30 January 2020
                2020
                : 11
                : 595
                Affiliations
                [1 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Neurology and Hertie-Institute for Clinical Brain Research, , University of Tübingen, ; Tübingen, Germany
                [2 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, German Center of Neurodegenerative Diseases (DZNE), ; Tübingen, Germany
                [3 ]ISNI 0000 0004 0367 4692, GRID grid.414735.0, Institute of Medical Biology, A*STAR, Biopolis, ; Singapore, 138648 Singapore
                [4 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, National University of Singapore, Department of Paediatrics, , Yong Loo Lin School of Medicine, Biopolis, ; Singapore, Singapore
                [5 ]ISNI 0000 0001 2173 6074, GRID grid.40803.3f, Department of Molecular and Structural Biochemistry North Carolina State University, ; Raleigh, NC 27607 USA
                [6 ]ISNI 0000 0004 4651 0380, GRID grid.463064.3, Yale-NUS College, 12 College Avenue West, Biopolis, ; Singapore, Singapore
                [7 ]ISNI 0000000122986657, GRID grid.34477.33, Division of Medical Genetics, Department of Medicine, , University of Washington, ; Seattle, WA USA
                [8 ]ISNI 0000 0001 2181 7253, GRID grid.413784.d, Service De Biochimie, , Hopital Bicêtre, Assistance publique-Hôpitaux de Paris, 78 avenue du general leclerc, ; Le Kremlin Bicêtre, France
                [9 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Institute of Medical Biology, , Singapore Stem Cell Bank, A∗STAR, Biopolis, ; Singapore, 138648 Singapore
                [10 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Translational Laboratory in Genetic Medicine, Agency for Science, , Technology, and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, ; Singapore, 138648 Singapore
                [11 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics, , The University of Toronto, ; Toronto, ON Canada
                [12 ]Caritas Baby Hospital Bethlehem, Bethlehem, State of Palestine
                [13 ]Ped Neurology, Staufer Hospital, Wetzgauer Straße 85, Schwäbisch-Gmünd, Germany
                [14 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, McKusick-Nathans Institute of Genetic Medicine, , Johns Hopkins University School of Medicine, ; Baltimore, MD 21205 USA
                [15 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Paediatric Neurology, , Ghent University Hospital, ; Ghent, Belgium
                [16 ]ISNI 0000000104788040, GRID grid.11486.3a, Center for Molecular Neurology, VIB, ; Antwerp, Belgium
                [17 ]ISNI 0000 0001 0790 3681, GRID grid.5284.b, Laboratory of Neurogenetics, Institute Born-Bunge, , University of Antwerp, ; Antwerp, Belgium
                [18 ]ISNI 0000 0004 0626 3418, GRID grid.411414.5, Department of Neurology, , University Hospital Antwerp, ; Antwerp, Belgium
                [19 ]ISNI 0000 0004 0427 667X, GRID grid.240023.7, Division of Neurology and Neurogenetics, , Kennedy Krieger Institute, ; Baltimore, MD USA
                [20 ]ISNI 0000 0000 8958 3388, GRID grid.414963.d, Neurology Service, Department of Paediatrics, , KK Women’s and Children’s Hospital, ; Singapore, Singapore
                [21 ]ISNI 0000 0000 8958 3388, GRID grid.414963.d, Genetics Service, Department of Paediatrics, , KK Women’s and Children’s Hospital, ; Singapore, Singapore
                [22 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Paediatric Academic Clinical Programme, , Duke-NUS Medical School, ; Singapore, Singapore
                [23 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, SingHealth Duke-NUS Genomic Medicine Centre, ; Singapore, Singapore
                [24 ]ISNI 0000 0001 2322 4179, GRID grid.410528.a, Service de Génétique Médicale, , CHU De Nice Hôpital de l’Archet 2, 151 route Saint Antoine de la Ginestière, CS 23079 062002, ; Nice, Cedex 3 France
                [25 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Pediatric Neurology, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [26 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Genetics, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [27 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Neurology Division, Childrens Hospital Los Angeles & Department of Neurology, , Keck School of Medicine of University of Southern California, ; Los Angeles, CA 90033 USA
                [28 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, , Cedars-Sinai Medical Center, ; Los Angeles, CA USA
                [29 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Genetics and Genomic Medicine, Department of Pediatrics, , Washington University School of Medicine, ; St. Louis, MO USA
                [30 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Genetics and Genomics and Department of Neurology, , Boston Children’s Hospital, ; Boston, MA USA
                [31 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Clinical Genetics, Erasmus MC, , University Medical Center, Wytemaweg 80, ; 3015 CN Rotterdam, The Netherlands
                [32 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Clinical Genomics, , Mayo Clinic, ; 200 First Street SW, Rochester, MN USA
                [33 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Genetics and Rare Diseases Research Division, , Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, ; 00146 Rome, Italy
                [34 ]ISNI 0000 0001 2221 2926, GRID grid.17788.31, Child Neurology Unit, , Hadassah-Hebrew University Medical Center, ; 9112001 Jerusalem, Israel
                [35 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, Pediatric Neurology, , King Faisal Specialist Hospital and Research Center, ; Riyadh, Saudi Arabia
                [36 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, Department of Genetics, , King Faisal Specialist Hospital and Research Center, ; Riyadh, Saudi Arabia
                [37 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, Department of Medical Genetics, , King Faisal Specialist Hospital and Research Center, ; Riyadh, Saudi Arabia
                [38 ]Department of Pediatrics, King Fahad Central Hospital in Jizan, Abu Arish, Saudi Arabia
                [39 ]ISNI 0000 0004 0593 1832, GRID grid.415277.2, Pediatric Neurology Department, National Neuroscience Institute, , King Fahad Medical City, ; Riyadh, Saudi Arabia
                [40 ]ISNI 0000 0004 0593 1832, GRID grid.415277.2, Section of Medical Genetics, , Children’s Hospital, King Fahad Medical City, ; Riyadh, Saudi Arabia
                [41 ]ISNI 0000 0004 0593 1832, GRID grid.415277.2, General Pediatrics and Adolescents, , King Fahad Medical City, ; Riyadh, Saudi Arabia
                [42 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, Neuroscience Department King Faisal Specialist Hospital and Research Center, ; Riyadh, Saudi Arabia
                [43 ]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Division of Neurology, , The Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [44 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Human Genetics, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [45 ]Institute of Medical Genetics and Applied Genomics (Tübingen) and Centogene AG (Rostock), Rostock, Germany
                [46 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Pediatric Neurology, , University of Tübingen, ; Tübingen, Germany
                [47 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Institute of Molecular and Cell Biology, , A*STAR, Biopolis, ; Singapore, 138673 Singapore
                [48 ]ISNI 0000 0004 0455 211X, GRID grid.465138.d, Division of Clinical Genomics, Ambry Genetics, ; Aliso Viejo, CA USA
                [49 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, APHP, GH Pitié Salpêtrière, Department of Genetics, Unit of Development Genomics, ; Paris, France
                [50 ]ISNI 0000 0001 2221 2926, GRID grid.17788.31, Department of Genetic and Metabolic Diseases, , Hadassah-Hebrew University Medical Center, ; 9112001 Jerusalem, Israel
                [51 ]GRID grid.428467.b, GeneDx, 207 Perry Parkway, ; Gaithersburg, MD 20877 USA
                [52 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Physiology, , National University of Singapore, ; Singapore, 117597 Singapore
                [53 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Medicine, , National University of Singapore, ; Singapore, 117597 Singapore
                [54 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Program in Neuroscience and Behavioral Disorders, , Duke-NUS Medical School, ; Singapore, Singapore
                [55 ]Department of Neurology, Donders Center for Brain, Cognition, and Behavior, Nijmegen, The Netherlands
                [56 ]Department of Laboratory Medicine, Translational Metabolic Laboratory, Nijmegen, The Netherlands
                [57 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, SingHealth Duke-NUS Institute of Precision Medicine, ; Singapore, Singapore
                [58 ]ISNI 0000000106887552, GRID grid.15876.3d, Medical Genetics Department, , Koç University School of Medicine, ; 34010 Istanbul, Turkey
                [59 ]ISNI 0000000404654431, GRID grid.5650.6, Reproductive Biology Laboratory, Obstetrics and Gynaecology, , Academic Medical Center (AMC), Meibergdreef 9, ; 1105 AZ Amsterdam-Zuidoost, The Netherlands
                Author information
                http://orcid.org/0000-0002-9773-2667
                http://orcid.org/0000-0003-0419-8547
                http://orcid.org/0000-0002-7146-617X
                http://orcid.org/0000-0003-1985-3671
                http://orcid.org/0000-0002-5448-1204
                http://orcid.org/0000-0003-1231-1562
                http://orcid.org/0000-0003-3060-422X
                http://orcid.org/0000-0001-8486-0558
                http://orcid.org/0000-0002-3897-1238
                http://orcid.org/0000-0002-7222-9985
                http://orcid.org/0000-0002-7307-388X
                http://orcid.org/0000-0003-4158-341X
                http://orcid.org/0000-0003-4591-5274
                http://orcid.org/0000-0003-3620-0277
                http://orcid.org/0000-0002-4070-7997
                Article
                14360
                10.1038/s41467-020-14360-7
                6992768
                32001716
                f676c826-e2ce-4ecb-98ad-840f498c5bd9
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 September 2017
                : 19 December 2019
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                © The Author(s) 2020

                Uncategorized
                glycobiology,clinical genetics,neuronal development,encephalopathy
                Uncategorized
                glycobiology, clinical genetics, neuronal development, encephalopathy

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