@article{ee6526884cd14bab80cedd3163914f3c,
title = "Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients",
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 H3F36 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.",
keywords = "PHOSPHORYLATION, TRANSCRIPTION, VARIANTS, RESIDUE, GENES, CODE",
author = "Laura Bryant and Dong Li and Cox, {Samuel G.} and Dylan Marchione and Joiner, {Evan F.} and Khadija Wilson and Kevin Janssen and Pearl Lee and March, {Michael E.} and Divya Nair and Elliott Sherr and Brieana Fregeau and Wierenga, {Klaas J.} and Alexandrea Wadley and Mancini, {Grazia M. S.} and Nina Powell-Hamilton and {van de Kamp}, Jiddeke and Theresa Grebe and John Dean and Alison Ross and Crawford, {Heather P.} and Zoe Powis and Cho, {Megan T.} and Willing, {Marcia C.} and Linda Manwaring and Rachel Schot and Caroline Nava and Alexandra Afenjar and Davor Lessel and Matias Wagner and Thomas Klopstock and Juliane Winkelmann and Catarino, {Claudia B.} and Kyle Retterer and Schuette, {Jane L.} and Innis, {Jeffrey W.} and Amy Pizzino and Sabine Luttgen and Jonas Denecke and Strom, {Tim M.} and Monaghan, {Kristin G.} and Zuo-Fei Yuan and Holly Dubbs and Renee Bend and Lee, {Jennifer A.} and Lyons, {Michael J.} and Julia Hoefele and Stumpel, {Constance T. R. M.} and Stevens, {Servi J. C.} and Stegmann, {Alexander P. A.} and {DDD Study} and {Care4Rare Canada Consortium} and {CAUSES Study} and Elizabeth Bhoj",
note = "Funding Information: Funding was provided by the French Foundation for Rare Diseases (Fondation maladies rares). 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.). 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). Funding from NIH grants GM110174 and CA196539 to B.G. is acknowledged. 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. 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. 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 Ges? (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) to M.T. Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved;",
year = "2020",
month = dec,
doi = "10.1126/sciadv.abc9207",
language = "English",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "49",
}