@article{7224a6d323a24348a7216666bf581698,
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 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.",
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 L{\"u}ttgen 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 Christina Fagerberg and Laulund, \{Lone Walentin\} and Larsen, \{Martin J\} and \{DDD Study\}",
note = "Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",
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",
}