Journal article

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

  • Acuna-Hidalgo R Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Deriziotis P Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
  • Steehouwer M Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Gilissen C Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Graham SA Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
  • van Dam S University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
  • Hoover-Fong J McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
  • Telegrafi AB GeneDx, Gaithersburg, Maryland, United States of America.
  • Destree A Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
  • Smigiel R Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland.
  • Lambie LA Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • Kayserili H Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.
  • Altunoglu U Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
  • Lapi E Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.
  • Uzielli ML University of Florence, Genetic Science, Firenze, Italy.
  • Aracena M División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile.
  • Nur BG Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.
  • Mihci E Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.
  • Moreira LM Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil.
  • Borges Ferreira V Hospital Santa Izabel, Salvador-Bahia, Brazil.
  • Horovitz DD CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil.
  • da Rocha KM Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil.
  • Jezela-Stanek A Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
  • Brooks AS Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.
  • Reutter H Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
  • Cohen JS Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.
  • Fatemi A Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.
  • Smitka M Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
  • Grebe TA Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, United States of America.
  • Di Donato N Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
  • Deshpande C Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
  • Vandersteen A North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom.
  • Marques Lourenço C Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
  • Dufke A Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Rossier E Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Andre G Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France.
  • Baumer A Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
  • Spencer C Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • McGaughran J Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
  • Franke L University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
  • Veltman JA Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
  • De Vries BB Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Schinzel A Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
  • Fisher SE Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
  • Hoischen A Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • van Bon BW Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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  • 2017-03-28
Published in:
  • PLoS genetics. - 2017
English Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple 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 information 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. Substitutions 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 cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/266551
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