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Bryant, L.* ; Li, D.* ; Cox, S.G.* ; Marchione, D.* ; Joiner, E.F.* ; Wilson, K.* ; Janssen, K.* ; Lee, P.* ; March, M.E.* ; Nair, D.* ; Sherr, E.* ; Fregeau, B.* ; Wierenga, K.J.* ; Wadley, A.* ; Mancini, G.M.S.* ; Powell-Hamilton, N.* ; van de Kamp, J.M.* ; Grebe, T.* ; Dean, J.* ; Ross, A.* ; Crawford, H.P.* ; Powis, Z.* ; Cho, M.T.* ; Willing, M.C.* ; Manwaring, L.* ; Schot, R.* ; Nava, C.* ; Afenjar, A.* ; Lessel, D.* ; Wagner, M. ; Klopstock, T.* ; Winkelmann, J. ; Catarino, C.B.* ; Retterer, K.* ; Schuette, J.L.* ; Innis, J.W.* ; Pizzino, A.* ; Lüttgen, S.* ; Denecke, J.* ; Strom, T.M. ; Monaghan, K.G.* ; Yuan, Z.F.* ; Dubbs, H.* ; Bend, R.* ; Lee, J.A.* ; Lyons, M.J.* ; Hoefele, J.* ; Günthner, R.* ; Reutter, H.* ; Keren, B.* ; Radtke, K.* ; Sherbini, O.* ; Mrokse, C.* ; Helbig, K.L.* ; Odent, S.* ; Cogné, B.* ; Mercier, S.* ; Bézieau, S.* ; Besnard, T.* ; Küry, S.* ; Redon, R.* ; Reinson, K.* ; Wojcik, M.H.* ; Õunap, K.* ; Ilves, P.* ; Innes, A.M.* ; Kernohan, K.D.* ; Costain, G.* ; Meyn, M.S.* ; Chitayat, D.* ; Zackai, E.* ; Lehman, A.* ; Kitson, H.* ; Martin, M.G.* ; Martinez-Agosto, J.A.* ; Nelson, S.F.* ; Palmer, C.G.S.* ; Papp, J.C.* ; Parker, N.H.* ; Sinsheimer, J.S.* ; Vilain, E.* ; Wan, J.* ; Yoon, A.J.* ; Zheng, A.* ; Brimble, E.* ; Ferrero, G.B.* ; Radio, F.C.* ; Carli, D.* ; Barresi, S.* ; Brusco, A.* ; Tartaglia, M.* ; Thomas, J.M.* ; Umana, L.* ; Weiss, M.M.* ; Gotway, G.* ; Stuurman, K.E.* ; Thompson, M.L.* ; McWalter, K.* ; Stumpel, C.T.R.M.* ; Stevens, S.J.C.* ; Stegmann, A.P.A.* ; Tveten, K.* ; Vøllo, A.* ; Prescott, T.* ; Fagerberg, C.* ; Laulund, L.W.* ; Larsen, M.J.* ; Byler, M.* ; Lebel, R.R.* ; Hurst, A.C.* ; Schrier Vergano, S.A.* ; Norman, J.* ; Mercimek-Andrews, S.* ; Neira, J.* ; Van Allen, M.I.* ; Longo, N.* ; Sellars, E.* ; Louie, R.J.* ; Cathey, S.S.* ; Brokamp, E.* ; Heron, D.* ; Snyder, M.* ; Vanderver, A.* ; Simon, C.* ; de la Cruz, X.* ; Padilla, N.* ; Crump, J.G.* ; Chung, W.* ; Garcia, B.* ; Hakonarson, H.H.* ; Bhoj, E.J.*

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

Sci. Adv. 6:106267 (2020)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Phosphorylation; Transcription; Variants; Residue; Genes; Code
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Quellenangaben Volume: 6, Issue: 49, Pages: , Article Number: 106267 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Grants Italian Ministry of Health
National Human Genome Research Institute
Estonian Science Foundation
T32 training grant
Roberts Collaborative
K12 training grant
NIDDK T35 training grant
JPB Foundation
National Eye Institute
National Heart, Lung, and Blood Institute
Fondazione Bambino Gesu (Vite Coraggiose)
Dipartimenti di Eccellenza 2018-2022 Project
Children's Hospital of Eastern Ontario Foundation
Genome Quebec
Ontario Research Fund
Ontario Genomics Institute
Canadian Institutes of Health Research
Genome Canada
Norman Saunders Complex Care Initiative
Centre for Applied Genomics
Centre for Genetic Medicine
Alabama Genomic Health Initiative through University of Alabama at Birmingham IRB
French Foundation for Rare Diseases (Fondation maladies rares)