Histone H3.3 beyond cancer : Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
Bryant, Laura (Children's Hospital of Philadelphia (Pennsilvània))
Li, Dong (Children's Hospital of Philadelphia (Pennsilvània))
Cox, Samuel G. (University of Southern California, CA 90033, USA)
Marchione, Dylan (Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
Joiner, Evan F. (Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA)
Wilson, Khadija (Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
Janssen, Kevin (Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
Lee, Pearl (Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
March, Michael E. (Children's Hospital of Philadelphia (Pennsilvània))
Nair, Divya (Children's Hospital of Philadelphia (Pennsilvània))
Sherr, Elliott (Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA)
Fregeau, Brieana (Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA)
Wierenga, Klaas J. (Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, USA)
Wadley, Alexandrea (Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, USA)
Mancini, Grazia M. S. (Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands)
Powell-Hamilton, Nina (Department of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE 19810, USA)
van de Kamp, Jiddeke (Department of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands)
Grebe, Theresa (Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA)
Dean, John (Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK)
Ross, Alison (Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK)
Crawford, Heather P. (Clinical and Metabolic Genetics, Cook Children's Medical Center, Fort Worth, TX 76104, USA)
Powis, Zoe (Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, CA 92656, USA)
Cho, Megan T. (GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA)
Willing, Marcia C. (Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA)
Manwaring, Linda (Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA)
Schot, Rachel (Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands)
Nava, Caroline (AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France)
Afenjar, Alexandra (Service de génétique, CRMR des malformations et maladies congénitales du cervelet et CRMR déficience intellectuelle, hôpital Trousseau, AP-HP, France)
Lessel, Davor (Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistrasse 52, 20246 Hamburg, Germany)
Wagner, Matias (Institut für Humangenetik, Technische Universität München, Munich, Germany)
Klopstock, Thomas (Munich Cluster for Systems Neurology, SyNergy, Munich, Germany)
Winkelmann, Juliane (Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany)
Catarino, Claudia B. (Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians University, Ziemssenstr. 1a, 80336 Munich, Germany)
Retterer, Kyle (GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA)
Schuette, Jane L. (Division of Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA)
Innis, Jeffrey W. (Division of Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA)
Pizzino, Amy (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA)
Lüttgen, Sabine (Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany)
Denecke, Jonas (Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany)
Strom, Tim M. (Institut für Humangenetik, Technische Universität München, Munich, Germany)
Monaghan, Kristin G. (GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA)
Yuan, Zuo-Fei (Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
Dubbs, Holly (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA)
Bend, Renee (Greenwood Genetic Center, Greenwood, SC 29646, USA)
Lee, Jennifer A. (Greenwood Genetic Center, Greenwood, SC 29646, USA)
Lyons, Michael J. (Greenwood Genetic Center, Greenwood, SC 29646, USA)
Hoefele, Julia (Technische Universität München. Institut für Humangenetik)
Günthner, Roman (Technische Universität München. Institut für Humangenetik)
Reutter, Heiko (Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University Hospital Bonn & Institute of Human Genetics, University Hospital Bonn, Bonn, Germany)
Keren, Boris (AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France)
Radtke, Kelly (Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA)
Sherbini, Omar (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA)
Mrokse, Cameron (Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA)
Helbig, Katherine L. (Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA)
Odent, Sylvie (CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, University Rennes1, Rennes, France)
Cogne, Benjamin (Université de Nantes)
Mercier, Sandra (Université de Nantes)
Bezieau, Stephane (Université de Nantes)
Besnard, Thomas (Université de Nantes)
Kury, Sebastien (Université de Nantes)
Redon, Richard (Université de Nantes)
Reinson, Karit (Institute of Clinical Medicine, University of Tartu, Tartu, Estonia)
Wojcik, Monica H. (Broad Institute, Cambridge, MA 02142, USA)
Õunap, Katrin (Institute of Clinical Medicine, University of Tartu, Tartu, Estonia)
Ilves, Pilvi (Tartu University Hospital (Tartu, Estònia))
Innes, A. Micheil (Alberta Children's Hospital Research Institute)
Kernohan, Kristin D. (Newborn Screening Ontario (NSO), Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada)
Costain, Gregory (Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada)
Meyn, M. Stephen (The Center for Human Genomics and Precision Medicine, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA)
Chitayat, David (The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada)
Zackai, Elaine (Children's Hospital of Philadelphia (Pennsilvània))
Lehman, Anna (Department of Medical Genetics, University of British Columbia, Vancouver, Canada)
Kitson, Hilary (Department of Pediatrics, University of British Columbia, Vancouver, Canada)
Martin, Martin G. (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)
Martinez-Agosto, Julian A. (Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Nelson, Stan F. (Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Palmer, Christina G. S. (Institute for Society and Genetics, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Papp, Jeanette C. (Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Parker, Neil H. (David Geffen School of Medicine, Los Angeles, CA 90095, USA)
Sinsheimer, Janet S. (Institute for Society and Genetics, Departments of Human Genetics, Biomathematics, and Biostatistics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Vilain, Eric (Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA)
Wan, Jijun (Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Yoon, Amanda J. (Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Zheng, Allison (Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA)
Brimble, Elise (Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA 94305, USA)
Ferrero, Giovanni Battista (Department of Public Health and Pediatrics, University of Torino, Turin, Italy)
Radio, Francesca Clementina (Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy)
Carli, Diana (Department of Public Health and Pediatrics, University of Torino, Turin, Italy)
Barresi, Sabina (Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy)
Brusco, Alfredo (Department of Medical Sciences, University of Torino, Turin, Italy)
Tartaglia, Marco (Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy)
Thomas, Jennifer Muncy (Pediatrics and Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA)
Umana, Luis (Genetics and Metabolism, UT Southwestern Medical Center, Dallas, TX 75390, USA)
Weiss, Marjan M. (Department of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands)
Gotway, Garrett (Genetics and Metabolism, UT Southwestern Medical Center, Dallas, TX 75390, USA)
Stuurman, K. E. (Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands)
Thompson, Michelle L. (HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA)
McWalter, Kirsty (GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA)
Stumpel, Constance T. R. M. (Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands)
Stevens, Servi J. C. (Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands)
Stegmann, Alexander P. A. (Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands)
Tveten, Kristian (Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway)
Vøllo, Arve (Department of Pediatrics, Hospital of Østfold, 1714 Grålum, Norway)
Prescott, Trine (Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway)
Fagerberg, Christina (Odense University Hospital (Dinamarca))
Laulund, Lone Walentin (Odense University Hospital (Dinamarca))
Larsen, Martin J. (Odense University Hospital (Dinamarca))
Byler, Melissa (SUNY Upstate Medical University, Syracuse, NY 13210, USA)
Lebel, Robert Roger (SUNY Upstate Medical University, Syracuse, NY 13210, USA)
Hurst, Anna C. (University of Alabama at Birmingham, Birmingham, AL 35294, USA)
Dean, Joy (University of Alabama at Birmingham, Birmingham, AL 35294, USA)
Schrier Vergano, Samantha A. (Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk VA 23507, USA)
Norman, Jennifer (INTEGRIS Pediatric Neurology, Oklahoma City, OK 73112, USA)
Mercimek-Andrews, Saadet (Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada)
Neira, Juanita (Department of Human Genetics, Emory University, Atlanta, GA 30322, USA)
Van Allen, Margot I. (Medical Genetics Programs, Provincial Health Shared Services BC and Vancouver Island Health Shared Services BC, Canada)
Longo, Nicola (Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA)
Sellars, Elizabeth (University of Arkansas for Medical Sciences, Little Rock, AR 72701, USA)
Louie, Raymond J. (Greenwood Genetic Center, Greenwood, SC 29646, USA)
Cathey, Sara S. (Greenwood Genetic Center, Greenwood, SC 29646, USA)
Brokamp, Elly (Vanderbilt University, Nashville, TN 37203, USA)
Heron, Delphine (AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France)
Snyder, Molly (Child Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA)
Vanderver, Adeline (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA)
Simon, Celeste (Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA)
de la Cruz, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Padilla Sirera, Natàlia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Crump, J. Gage (Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, CA 90033, USA)
Chung, Wendy (Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA)
Garcia, Benjamin (Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA)
Hakonarson, Hakon (Children's Hospital of Philadelphia (Pennsilvània))
Bhoj, Elizabeth J. (Children's Hospital of Philadelphia (Pennsilvània))
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Science advances, Vol. 6 (december 2020) , ISSN 2375-2548

DOI: 10.1126/sciadv.abc9207
PMID: 33268356

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