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

• Type of Material: Article
• Authors: Laura Bryant, Childrens Hospital of Philadelphia; Dong Li, Childrens Hospital of Philadelphia; Samuel G. Cox, University of Southern California; Dylan Marchione, University of Pennsylvania; Evan F. Joiner, Columbia University; Khadija Wilson, University of Pennsylvania; Kevin Janssen, University of Pennsylvania; Pearl Lee, University of Pennsylvania; Michael E. March, Childrens Hospital of Philadelphia; Divya Nair, Childrens Hospital of Philadelphia; Elliott Sherr, University of California San Francisco; Brieana Fregeau, University of California San Francisco; Klaas J. Wierenga, Mayo Clinic Florida; Alexandrea Wadley, Mayo Clinic Florida; Grazia M. S. Mancini, Erasmus Medical Center; Nina Powell-Hamilton, Alfred I duPont Hospital for Children; Jiddeke van de Kamp, Vrije Universiteit Amsterdam; Theresa Grebe, Phoenix Childrens Hospital; Juanita Neira, Emory University; Elizabeth J. Bhoj, Childrens Hospital of Philadelphia
• Language: English
• Date: 2020-12-01
• Publisher: American Association for the Advancement of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abc9207
• Title of Journal or Parent Work: Science Advances
• Volume: 6
• Issue: 49
• Grant/Funding Information: Funding from NIH grants GM110174 and CA196539 to B.G. is acknowledged.; The Care4Rare Canada Consortium is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation.; This work was also supported by Dipartimenti di Eccellenza 2018–2022 Project code D15D18000410001 to A.B. and Fondazione Bambino Gesù (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) to M.T.; E.J.B. was supported by a K12 training grant (K12HD043245-14) and the Roberts Collaborative. D.M. was supported by a T32 training grant (T32GM008275).; This research was funded in part by the Estonian Science Foundation grant PUT0355 and PRG471. Analysis for one patient was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 to D. MacArthur and H. Rehm.; Funding was provided by the French Foundation for Rare Diseases (Fondation maladies rares).; Support also provided by NIH T32 HD07466 (to M.H.W.), Alabama Genomic Health Initiative F170303004 through University of Alabama at Birmingham IRB (to A.C.H., J.D., and M.T.) The Toronto-based authors (to G.C., M.S.M., and D.C.) acknowledge support from the Centre for Genetic Medicine, The Centre for Applied Genomics, and the Norman Saunders Complex Care Initiative.; This work was also supported in part by a grant from the from SFARI (to W.K.C.), JPB Foundation (to W.K.C.), and the Morton S. and Henrietta K. Sellner Professorship in Human Genetics (to J.W.I.), as well as an NIDDK T35 training grant (T35DK093430) (to E.F.J.).
• Keywords: Variants; Transcription; Code; Science & Technology - Other Topics; Science & Technology; Residue; Phosphorylation; Genes; Multidisciplinary Sciences
• Research Categories: Biology, Genetics; Biology, Neuroscience; Biology, Cell; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

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.