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Overlapping SETBP1 Gain-Of-Function Mutations in Schinzel-Giedion Syndrome and Hematologic Malignancies

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Overlapping SETBP1 Gain-Of-Function Mutations in Schinzel-Giedion Syndrome and Hematologic Malignancies Acuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LMA, Borges Ferreira V, Horovitz DDG, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenco C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BBA, Schinzel A, Fisher SE, Hoischen A, van Bon BW. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genetics 2017, 13(3), e1006683. Copyright: © 2017 Acuna-Hidalgo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI link to article: https://doi.org/10.1371/journal.pgen.1006683 Date deposited: 03/05/2017 This work is licensed under a Creative Commons Attribution 4.0 International License Newcastle University ePrints - eprint.ncl.ac.uk RESEARCH ARTICLE Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies Rocio Acuna-Hidalgo1☯, Pelagia Deriziotis2☯, Marloes Steehouwer1, Christian Gilissen1,3, Sarah A. Graham2, Sipko van Dam4, Julie Hoover-Fong5, Aida B. Telegrafi6, Anne Destree7, Robert Smigiel8, Lindsday A. Lambie9, HuÈ lya Kayserili10, Umut Altunoglu11, Elisabetta Lapi12, Maria Luisa Uzielli13, Mariana Aracena14, Banu G. Nur15, Ercan Mihci15, Lilia M. A. Moreira16, Viviane Borges Ferreira17, Dafne D. a1111111111 G. Horovitz18, Katia M. da Rocha19, Aleksandra Jezela-Stanek20, Alice S. Brooks21, a1111111111 Heiko Reutter22, Julie S. Cohen23, Ali Fatemi23, Martin Smitka24, Theresa A. Grebe25, a1111111111 Nataliya Di Donato26, Charu Deshpande27, Anthony Vandersteen28, Charles Marques 29 30 30 31 32 a1111111111 LourencËo , Andreas Dufke , Eva Rossier , Gwenaelle Andre , Alessandra Baumer , 9 33 4 3,34 a1111111111 Careni Spencer , Julie McGaughran , Lude Franke , Joris A. Veltman , Bert B. A. De Vries1,3, Albert Schinzel32, Simon E. Fisher2,35, Alexander Hoischen1,3,36³*, Bregje W. van Bon1³* 1 Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands, 2 Language and Genetics Department, Max Planck Institute for OPEN ACCESS Psycholinguistics, Nijmegen, The Netherlands, 3 Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands, 4 University of Groningen, Citation: Acuna-Hidalgo R, Deriziotis P, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands, 5 McKusick- Steehouwer M, Gilissen C, Graham SA, van Dam S, Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of et al. (2017) Overlapping SETBP1 gain-of-function America, 6 GeneDx, Gaithersburg, Maryland, United States of America, 7 Institute of Pathology and mutations in Schinzel-Giedion syndrome and Genetics (IPG), Gosselies, Belgium, 8 Department of Pediatrics and Rare Disorders, Medical University, hematologic malignancies. PLoS Genet 13(3): Wroclaw, Poland, 9 Division of Human Genetics, National Health Laboratory Service and School of e1006683. https://doi.org/10.1371/journal. Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, pgen.1006683 10 Medical Genetics Department, KocË University School of Medicine (KUSOM), İstanbul, Turkey, 11 Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey, 12 Medical Genetics Editor: Gregory S. Barsh, Stanford University Unit, Anna Meyer Children's University Hospital, Florence, Italy, 13 University of Florence, Genetic Science, School of Medicine, UNITED STATES Firenze, Italy, 14 DivisioÂn de PediatrõÂa, Pontificia Universidad CatoÂlica de Chile and Unidad de GeneÂtica, Hospital Dr. Luis Calvo Mackenna, Santiago Chile, 15 Department of Pediatric Genetics, Akdeniz University Received: September 17, 2016 Medical School, Antalya, Turkey, 16 Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil, 17 Hospital Santa Izabel, Salvador-Bahia, Brazil, 18 CERES-Genetica Accepted: March 10, 2017 Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Published: March 27, 2017 Brazil, 19 Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil, 20 Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland, 21 Department Copyright: © 2017 Acuna-Hidalgo et al. This is an of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands, 22 Institute of open access article distributed under the terms of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric the Creative Commons Attribution License, which Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany, 23 Division of Neurogenetics, permits unrestricted use, distribution, and Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, reproduction in any medium, provided the original Maryland, United States of America, 24 Abteilung NeuropaÈdiatrie, Medizinische FakultaÈt Carl Gustav Carus, Technische UniversitaÈt Dresden, Germany, 25 Division of Genetics & Metabolism, Phoenix Children's author and source are credited. Hospital, Phoenix, Arizona, United States of America, 26 Institute for Clinical Genetics, TU Dresden, Data Availability Statement: All relevant data are Dresden, Germany, 27 Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, within the paper and its Supporting Information United Kingdom, 28 North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West files. London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom, 29 Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Funding: RAH received a PhD grant from the Sao Paulo, Sao Paulo, Brazil, 30 Institute of Medical Genetics and Applied Genomics, University of Radboud University Medical Center. PD, SAG and TuÈbingen, TuÈbingen, Germany, 31 Unite de foetopathologie, HoÃpital Pellegrin, Place AmeÂlie Raba LeÂon, SEF were supported by funding from the Max Bordeaux, France, 32 Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland, 33 Genetic Planck Society. SvD and LF were supported by Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia, 34 Institute of Genetic Medicine, funding from the European Research Council (ERC International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom, 35 Donders Starting Grant agreement number 637640 Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands, 36 Department ImmRisk to LF), in addition to a VIDI grant PLOS Genetics | https://doi.org/10.1371/journal.pgen.1006683 March 27, 2017 1 / 25 Overlapping germline and somatic mutations in SETBP1 (917.14.374) from the Netherlands Organization of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, for Scientific Research (NWO) to LF. This work was Nijmegen, The Netherlands in part financially supported by grants from the Netherlands Organization for Scientific Research ☯ These authors contributed equally to this work. (918-15-667 to JAV) and the European Research ³ AH and BWvB also contributed equally to this work. * [email protected] (BWvB); [email protected] (AH) Council (ERC Starting grant DENOVO 281964 to JAV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Abstract Competing interests: The authors have declared that no competing interests exist. Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multi- ple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical infor- mation of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Sub- stitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of
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