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

Laura Bryant, Dong Li, Samuel G. Cox, Dylan Marchione, Evan F. Joiner, Khadija Wilson, Kevin Janssen, Pearl Lee, Michael E. March, Divya Nair, Elliott Sherr, Brieana Fregeau, Klaas J. Wierenga, Alexandrea Wadley, Grazia M. S. Mancini, Nina Powell-Hamilton, Jiddeke van de Kamp, Theresa Grebe, John Dean, Alison RossHeather P. Crawford, Zoe Powis, Megan T. Cho, Marcia C. Willing, Linda Manwaring, Rachel Schot, Caroline Nava, Alexandra Afenjar, Davor Lessel, Matias Wagner, Thomas Klopstock, Juliane Winkelmann, Claudia B. Catarino, Kyle Retterer, Jane L. Schuette, Jeffrey W. Innis, Amy Pizzino, Sabine Luttgen, Jonas Denecke, Tim M. Strom, Kristin G. Monaghan, Zuo-Fei Yuan, Holly Dubbs, Renee Bend, Jennifer A. Lee, Michael J. Lyons, Julia Hoefele, Constance T. R. M. Stumpel, Servi J. C. Stevens, Alexander P. A. Stegmann, DDD Study, Care4Rare Canada Consortium, CAUSES Study, Elizabeth Bhoj*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number9207
Number of pages11
JournalScience advances
Issue number49
Publication statusPublished - Dec 2020


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