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.
GrantsItalian Ministry of Health National Human Genome Research Institute Estonian Science Foundation NIH T32 training grant Roberts Collaborative K12 training grant NIDDK T35 training grant JPB Foundation SFARI 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)