Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients - Sorbonne Université Access content directly
Journal Articles Science Advances Year : 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 , 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 Ross , Heather P Crawford , Zoe Powis , Megan T Cho , Marcia C Willing , Linda Manwaring , Rachel Schot , Caroline Nava (1) , Alexandra Afenjar (2) , Davor Lessel , Matias Wagner , Thomas Klopstock , Juliane Winkelmann , Claudia B Catarino , Kyle Retterer , Jane L Schuette , Jeffrey W Innis , Amy Pizzino , Sabine Lüttgen , Jonas Denecke , Tim M Strom , Kristin G Monaghan , Zuo-Fei Yuan , Holly Dubbs , Renee Bend , Jennifer A Lee , Michael J Lyons , Julia Hoefele , Roman Günthner , Heiko Reutter , Boris Keren , Kelly Radtke , Omar Sherbini , Cameron Mrokse , Katherine L Helbig , Sylvie Odent (3) , Benjamin Cogne (4, 5) , Sandra Mercier (4, 5) , Stephane Bezieau (4, 5) , Thomas Besnard (4, 5) , Sebastien Kury (4, 5) , Richard Redon (5) , Karit Reinson , Monica H Wojcik , Katrin Õunap , Pilvi Ilves , A. Micheil Innes , Kristin D Kernohan , Gregory Costain , M. Stephen Meyn , David Chitayat , Elaine Zackai , Anna Lehman , Hilary Kitson , Martin Martin , Julian A Martinez-Agosto , Stan F Nelson , Christina G S Palmer , Jeanette C Papp , Neil H Parker , Janet S Sinsheimer , Eric Vilain , Jijun Wan , Amanda J Yoon , Allison Zheng , Elise Brimble , Giovanni Battista Ferrero , Francesca Clementina Radio , Diana Carli , Sabina Barresi , Alfredo Brusco , Marco Tartaglia , Jennifer Muncy Thomas , Luis Umana , Marjan M Weiss , Garrett Gotway , K E Stuurman , Michelle L Thompson , Kirsty Mcwalter , Constance T R M Stumpel , Servi J C Stevens , Alexander P A Stegmann , Kristian Tveten , Arve Vøllo , Trine Prescott , Christina Fagerberg , Lone Walentin Laulund , Martin J Larsen , Melissa Byler , Robert Roger Lebel , Anna C Hurst , Joy Dean , Samantha A Schrier Vergano , Jennifer Norman , Saadet Mercimek-Andrews , Juanita Neira , Margot I van Allen , Nicola Longo , Elizabeth Sellars , Raymond J Louie , Sara S Cathey , Elly Brokamp , Delphine Heron (1) , Molly Snyder , Adeline Vanderver , Celeste Simon , Xavier de la Cruz , Natália Padilla , J. Gage Crump , Wendy Chung , Benjamin Garcia , Hakon H Hakonarson , Elizabeth J Bhoj
Laura Bryant
Dong Li
Samuel G Cox
  • Function : Author
Dylan Marchione
  • Function : Author
Evan F Joiner
  • Function : Author
Khadija Wilson
  • Function : Author
Kevin Janssen
  • Function : Author
Pearl Lee
  • Function : Author
Michael E March
  • Function : Author
Divya Nair
  • Function : Author
Elliott Sherr
Brieana Fregeau
  • Function : Author
Klaas J Wierenga
  • Function : Author
Alexandrea Wadley
  • Function : Author
Grazia M S Mancini
  • Function : Author
Nina Powell-Hamilton
  • Function : Author
Jiddeke van de Kamp
  • Function : Author
Theresa Grebe
  • Function : Author
John Dean
Alison Ross
  • Function : Author
Heather P Crawford
  • Function : Author
Zoe Powis
  • Function : Author
Megan T Cho
  • Function : Author
Marcia C Willing
  • Function : Author
Linda Manwaring
  • Function : Author
Rachel Schot
  • Function : Author
Davor Lessel
Matias Wagner
  • Function : Author
Thomas Klopstock
Juliane Winkelmann
  • Function : Author
Claudia B Catarino
  • Function : Author
Kyle Retterer
  • Function : Author
Jane L Schuette
  • Function : Author
Jeffrey W Innis
  • Function : Author
Amy Pizzino
  • Function : Author
Sabine Lüttgen
  • Function : Author
Jonas Denecke
  • Function : Author
Tim M Strom
  • Function : Author
Kristin G Monaghan
  • Function : Author
Zuo-Fei Yuan
  • Function : Author
Holly Dubbs
  • Function : Author
Renee Bend
  • Function : Author
Jennifer A Lee
  • Function : Author
Michael J Lyons
  • Function : Author
Julia Hoefele
  • Function : Author
Roman Günthner
  • Function : Author
Heiko Reutter
  • Function : Author
Boris Keren
  • Function : Author
Kelly Radtke
  • Function : Author
Omar Sherbini
  • Function : Author
Cameron Mrokse
  • Function : Author
Katherine L Helbig
  • Function : Author
Karit Reinson
  • Function : Author
Monica H Wojcik
  • Function : Author
Katrin Õunap
  • Function : Author
Pilvi Ilves
  • Function : Author
A. Micheil Innes
  • Function : Author
Kristin D Kernohan
  • Function : Author
Gregory Costain
  • Function : Author
M. Stephen Meyn
  • Function : Author
David Chitayat
  • Function : Author
Elaine Zackai
  • Function : Author
Anna Lehman
  • Function : Author
Hilary Kitson
  • Function : Author
Martin Martin
  • Function : Author
Julian A Martinez-Agosto
  • Function : Author
Stan F Nelson
  • Function : Author
Christina G S Palmer
  • Function : Author
Jeanette C Papp
  • Function : Author
Neil H Parker
  • Function : Author
Janet S Sinsheimer
  • Function : Author
Eric Vilain
  • Function : Author
Jijun Wan
  • Function : Author
Amanda J Yoon
  • Function : Author
Allison Zheng
  • Function : Author
Elise Brimble
  • Function : Author
Giovanni Battista Ferrero
  • Function : Author
Francesca Clementina Radio
  • Function : Author
Diana Carli
  • Function : Author
Sabina Barresi
  • Function : Author
Alfredo Brusco
Marco Tartaglia
  • Function : Author
Jennifer Muncy Thomas
  • Function : Author
Luis Umana
  • Function : Author
Marjan M Weiss
  • Function : Author
Garrett Gotway
  • Function : Author
K E Stuurman
  • Function : Author
Michelle L Thompson
  • Function : Author
Kirsty Mcwalter
Constance T R M Stumpel
  • Function : Author
Servi J C Stevens
Alexander P A Stegmann
  • Function : Author
Kristian Tveten
  • Function : Author
Arve Vøllo
  • Function : Author
Trine Prescott
  • Function : Author
Christina Fagerberg
  • Function : Author
Lone Walentin Laulund
  • Function : Author
Martin J Larsen
  • Function : Author
Melissa Byler
  • Function : Author
Robert Roger Lebel
  • Function : Author
Anna C Hurst
  • Function : Author
Joy Dean
  • Function : Author
Samantha A Schrier Vergano
  • Function : Author
Jennifer Norman
  • Function : Author
Saadet Mercimek-Andrews
  • Function : Author
Juanita Neira
  • Function : Author
Margot I van Allen
  • Function : Author
Nicola Longo
  • Function : Author
Elizabeth Sellars
  • Function : Author
Raymond J Louie
  • Function : Author
Sara S Cathey
  • Function : Author
Elly Brokamp
  • Function : Author
Molly Snyder
  • Function : Author
Adeline Vanderver
  • Function : Author
Celeste Simon
  • Function : Author
Xavier de la Cruz
  • Function : Author
Natália Padilla
  • Function : Author
J. Gage Crump
Wendy Chung
  • Function : Author
Benjamin Garcia
  • Function : Author
Hakon H Hakonarson
Elizabeth J Bhoj

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.
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Licence : CC BY NC - Attribution - NonCommercial

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hal-04504898 , version 1 (14-03-2024)

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Attribution - NonCommercial

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Laura Bryant, Dong Li, Samuel G Cox, Dylan Marchione, Evan F Joiner, et al.. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Science Advances , 2020, 6 (49), ⟨10.1126/sciadv.abc9207⟩. ⟨hal-04504898⟩
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