Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, CA 90033, USA.
Sci Adv. 2020 Dec 2;6(49). doi: 10.1126/sciadv.abc9207. Print 2020 Dec.
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 () or 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.
虽然组蛋白 3.3（H3.3）中的体细胞突变是癌症发生的已知驱动因素，但种系突变的作用仍未见报道。我们分析了 46 名患有新生殖系突变的患者，这些突变发生在组蛋白 3 家族 3A（）或 中，表现为进行性神经功能障碍和先天性异常，而无恶性肿瘤。对所有 37 种变体的分子建模表明，与 DNA、其他组蛋白和组蛋白伴侣蛋白的相互作用明显受到干扰。患者组蛋白翻译后修饰（PTM）分析显示，局部 PTM 模式明显异常，与导致全局 PTM 失调的体细胞赖氨酸突变不同。对患者细胞的 RNA 测序显示，与有丝分裂和细胞分裂相关的基因表达上调，细胞测定证实增殖能力增加。斑马鱼模型显示颅面异常和 Foxd3 衍生的胶质缺陷。这些数据表明，种系突变的机制与癌症相关的体细胞组蛋白突变不同，但可能集中在控制细胞增殖上。
