2. Academic Validation
  3. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

  • Sci Adv. 2020 Dec 2;6(49):eabc9207. doi: 10.1126/sciadv.abc9207.
Laura Bryant 1,  Dong Li 1,  Samuel G Cox 2,  Dylan Marchione 3,  Evan F Joiner 4,  Khadija Wilson 3,  Kevin Janssen 3,  Pearl Lee 5,  Michael E March 1,  Divya Nair 1,  Elliott Sherr 6,  Brieana Fregeau 6,  Klaas J Wierenga 7,  Alexandrea Wadley 7,  Grazia M S Mancini 8,  Nina Powell-Hamilton 9,  Jiddeke van de Kamp 10,  Theresa Grebe 11,  John Dean 12,  Alison Ross 12,  Heather P Crawford 13,  Zoe Powis 14,  Megan T Cho 15,  Marcia C Willing 16,  Linda Manwaring 16,  Rachel Schot 8,  Caroline Nava 17 18,  Alexandra Afenjar 19,  Davor Lessel 20 21,  Matias Wagner 22 23 24,  Thomas Klopstock 25 26 27,  Juliane Winkelmann 22 24 27 28,  Claudia B Catarino 25,  Kyle Retterer 15,  Jane L Schuette 29,  Jeffrey W Innis 29,  Amy Pizzino 30 31,  Sabine Lüttgen 32,  Jonas Denecke 32,  Tim M Strom 22 24,  Kristin G Monaghan 15,  DDD Study,  Zuo-Fei Yuan 3,  Holly Dubbs 30 31,  Renee Bend 33,  Jennifer A Lee 33,  Michael J Lyons 33,  Julia Hoefele 24,  Roman Günthner 34 35,  Heiko Reutter 36,  Boris Keren 18,  Kelly Radtke 37,  Omar Sherbini 30 31,  Cameron Mrokse 37,  Katherine L Helbig 37,  Sylvie Odent 38,  Benjamin Cogne 39 40,  Sandra Mercier 39 40,  Stephane Bezieau 39 40,  Thomas Besnard 39 40,  Sebastien Kury 39 40,  Richard Redon 40,  Karit Reinson 41 42,  Monica H Wojcik 43 44,  Katrin Õunap 41 42,  Pilvi Ilves 45,  A Micheil Innes 46,  Kristin D Kernohan 47 48,  Care4Rare Canada Consortium,  Gregory Costain 49,  M Stephen Meyn 49 50,  David Chitayat 49 51,  Elaine Zackai 52,  Anna Lehman 53,  Hilary Kitson 54,  CAUSES Study,  Martin G Martin 55 56,  Julian A Martinez-Agosto 57 58,  Undiagnosed Diseases Network,  Stan F Nelson 57 59,  Christina G S Palmer 57 60,  Jeanette C Papp 57,  Neil H Parker 61,  Janet S Sinsheimer 62,  Eric Vilain 63,  Jijun Wan 57,  Amanda J Yoon 57,  Allison Zheng 57,  Elise Brimble 64,  Giovanni Battista Ferrero 65,  Francesca Clementina Radio 66,  Diana Carli 65,  Sabina Barresi 66,  Alfredo Brusco 67,  Marco Tartaglia 66,  Jennifer Muncy Thomas 68,  Luis Umana 69,  Marjan M Weiss 10,  Garrett Gotway 69,  K E Stuurman 8,  Michelle L Thompson 70,  Kirsty McWalter 15,  Constance T R M Stumpel 71,  Servi J C Stevens 71,  Alexander P A Stegmann 71,  Kristian Tveten 72,  Arve Vøllo 73,  Trine Prescott 72,  Christina Fagerberg 74,  Lone Walentin Laulund 75,  Martin J Larsen 74,  Melissa Byler 76,  Robert Roger Lebel 76,  Anna C Hurst 77,  Joy Dean 77,  Samantha A Schrier Vergano 78,  Jennifer Norman 79,  Saadet Mercimek-Andrews 49,  Juanita Neira 80,  Margot I Van Allen 53 81,  Nicola Longo 82,  Elizabeth Sellars 83,  Raymond J Louie 33,  Sara S Cathey 33,  Elly Brokamp 84,  Delphine Heron 18,  Molly Snyder 85,  Adeline Vanderver 30 31,  Celeste Simon 4,  Xavier de la Cruz 86 87,  Natália Padilla 86,  J Gage Crump 2,  Wendy Chung 88,  Benjamin Garcia 2 3,  Hakon H Hakonarson 1,  Elizabeth J Bhoj 89
Affiliations

Affiliations

  • 1 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 2 Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, CA 90033, USA.
  • 3 Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
  • 5 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 7 Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
  • 8 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
  • 9 Department of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE 19810, USA.
  • 10 Department of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands.
  • 11 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 12 Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK.
  • 13 Clinical and Metabolic Genetics, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • 14 Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 15 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 16 Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
  • 17 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.
  • 18 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France.
  • 19 Service de génétique, CRMR des malformations et maladies congénitales du cervelet et CRMR déficience intellectuelle, hôpital Trousseau, AP-HP, France.
  • 20 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 21 Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistrasse 52, 20246 Hamburg, Germany.
  • 22 Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.
  • 23 Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
  • 24 Institut für Humangenetik, Technische Universität München, Munich, Germany.
  • 25 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians University, Ziemssenstr. 1a, 80336 Munich, Germany.
  • 26 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 27 Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
  • 28 Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 29 Division of Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
  • 30 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 31 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA.
  • 32 Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany.
  • 33 Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 34 Department of Nephrology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
  • 35 Institute of Human Genetics, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
  • 36 Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University Hospital Bonn & Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.
  • 37 Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 38 CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, University Rennes1, Rennes, France.
  • 39 CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France.
  • 40 INSERM, CNRS, UNIV Nantes, CHU Nantes, l'institut du thorax, 44007 Nantes, France.
  • 41 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
  • 42 Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
  • 43 Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 44 Broad Institute, Cambridge, MA 02142, USA.
  • 45 Radiology Department of Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
  • 46 Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 47 Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H8L1, Canada.
  • 48 Newborn Screening Ontario (NSO), Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • 49 Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 50 The Center for Human Genomics and Precision Medicine, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.
  • 51 The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 52 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 53 Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
  • 54 Department of Pediatrics, University of British Columbia, Vancouver, Canada.
  • 55 Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children's Hospital, Los Angeles, CA 90095, USA.
  • 56 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 57 Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 58 Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 59 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 60 Institute for Society and Genetics, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 61 David Geffen School of Medicine, Los Angeles, CA 90095, USA.
  • 62 Institute for Society and Genetics, Departments of Human Genetics, Biomathematics, and Biostatistics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
  • 63 Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
  • 64 Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA 94305, USA.
  • 65 Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
  • 66 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
  • 67 Department of Medical Sciences, University of Torino, Turin, Italy.
  • 68 Pediatrics and Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 69 Genetics and Metabolism, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 70 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 71 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands.
  • 72 Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
  • 73 Department of Pediatrics, Hospital of Østfold, 1714 Grålum, Norway.
  • 74 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 75 H.C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
  • 76 SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 77 University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 78 Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk VA 23507, USA.
  • 79 INTEGRIS Pediatric Neurology, Oklahoma City, OK 73112, USA.
  • 80 Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
  • 81 Medical Genetics Programs, Provincial Health Shared Services BC and Vancouver Island Health Shared Services BC, Canada.
  • 82 Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.
  • 83 University of Arkansas for Medical Sciences, Little Rock, AR 72701, USA.
  • 84 Vanderbilt University, Nashville, TN 37203, USA.
  • 85 Child Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 86 Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 87 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  • 88 Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 89 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. [email protected].
PMID: 33268356 DOI: 10.1126/sciadv.abc9207
Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

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