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

Anno:

2020

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 1, Dong Li 1, Samuel G Cox 2, Dylan Marchione 3, Evan F Joiner 4, Khadija Wilson 3, Kevin Janssen 3, Pearl Lee 5, Michael E March 1, Divya Nair 1, Elliott Sherr 6, Brieana Fregeau 6, Klaas J Wierenga 7, Alexandrea Wadley 7, Grazia M S Mancini 8, Nina Powell-Hamilton 9, Jiddeke van de Kamp 10, Theresa Grebe 11, John Dean 12, Alison Ross 12, Heather P Crawford 13, Zoe Powis 14, Megan T Cho 15, Marcia C Willing 16, Linda Manwaring 16, Rachel Schot 8, Caroline Nava 17 18, Alexandra Afenjar 19, Davor Lessel 20 21, Matias Wagner 22 23 24, Thomas Klopstock 25 26 27, Juliane Winkelmann 22 24 27 28, Claudia B Catarino 25, Kyle Retterer 15, Jane L Schuette 29, Jeffrey W Innis 29, Amy Pizzino 30 31, Sabine Lüttgen 32, Jonas Denecke 32, Tim M Strom 22 24, Kristin G Monaghan 15, DDD Study; Zuo-Fei Yuan 3, Holly Dubbs 30 31, Renee Bend 33, Jennifer A Lee 33, Michael J Lyons 33, Julia Hoefele 24, Roman Günthner 34 35, Heiko Reutter 36, Boris Keren 18, Kelly Radtke 37, Omar Sherbini 30 31, Cameron Mrokse 37, Katherine L Helbig 37, Sylvie Odent 38, Benjamin Cogne 39 40, Sandra Mercier 39 40, Stephane Bezieau 39 40, Thomas Besnard 39 40, Sebastien Kury 39 40, Richard Redon 40, Karit Reinson 41 42, Monica H Wojcik 43 44, Katrin Õunap 41 42, Pilvi Ilves 45, A Micheil Innes 46, Kristin D Kernohan 47 48, Care4Rare Canada Consortium; Gregory Costain 49, M Stephen Meyn 49 50, David Chitayat 49 51, Elaine Zackai 52, Anna Lehman 53, Hilary Kitson 54, CAUSES Study; Martin G Martin 55 56, Julian A Martinez-Agosto 57 58, Undiagnosed Diseases Network; Stan F Nelson 57 59, Christina G S Palmer 57 60, Jeanette C Papp 57, Neil H Parker 61, Janet S Sinsheimer 62, Eric Vilain 63, Jijun Wan 57, Amanda J Yoon 57, Allison Zheng 57, Elise Brimble 64, Giovanni Battista Ferrero 65, Francesca Clementina Radio 66, Diana Carli 65, Sabina Barresi 66, Alfredo Brusco 67, Marco Tartaglia 66, Jennifer Muncy Thomas 68, Luis Umana 69, Marjan M Weiss 10, Garrett Gotway 69, K E Stuurman 8, Michelle L Thompson 70, Kirsty McWalter 15, Constance T R M Stumpel 71, Servi J C Stevens 71, Alexander P A Stegmann 71, Kristian Tveten 72, Arve Vøllo 73, Trine Prescott 72, Christina Fagerberg 74, Lone Walentin Laulund 75, Martin J Larsen 74, Melissa Byler 76, Robert Roger Lebel 76, Anna C Hurst 77, Joy Dean 77, Samantha A Schrier Vergano 78, Jennifer Norman 79, Saadet Mercimek-Andrews 49, Juanita Neira 80, Margot I Van Allen 53 81, Nicola Longo 82, Elizabeth Sellars 83, Raymond J Louie 33, Sara S Cathey 33, Elly Brokamp 84, Delphine Heron 18, Molly Snyder 85, Adeline Vanderver 30 31, Celeste Simon 4, Xavier de la Cruz 86 87, Natália Padilla 86, J Gage Crump 2, Wendy Chung 88, Benjamin Garcia 2 3, Hakon H Hakonarson 1, Elizabeth J Bhoj 89

PMID: 33268356 PMCID: PMC7821880 DOI: 10.1126/sciadv.abc9207

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.