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
  • 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.