Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Commun. 2023 Jul 11;14(1):4109. doi: 10.1038/s41467-023-39645-5.
Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.
染色质调控因子中的遗传变异在神经发育障碍中经常被发现，但它们在疾病发病机制中的作用很少被确定。在这里，我们在 19 名个体中发现并功能定义了染色质修饰因子 EZH1 的致病性变异，这些变异是导致显性和隐性神经发育障碍的原因。EZH1 编码 PRC2 复合物中两种替代组蛋白 H3 赖氨酸 27 甲基转移酶之一。与其他参与癌症和发育综合征的 PRC2 亚基不同，EZH1 在人类发育和疾病中的作用在很大程度上是未知的。通过细胞和生化研究，我们证明隐性变异会损害 EZH1 的表达，从而导致功能丧失效应，而显性变异是错义突变，影响进化上保守的氨基酸，可能影响 EZH1 的结构或功能。因此，我们发现增加的甲基转移酶活性导致两种 EZH1 错义变异的功能获得。此外，我们发现 EZH1 对于鸡胚神经管中神经祖细胞的分化是必需和充分的。最后，我们使用人多能干细胞衍生的神经培养物和前脑类器官，证明 EZH1 变体扰乱了皮质神经元的分化。总的来说，我们的工作揭示了 EZH1 在神经发生调控中的关键作用，并为以前未定义的神经发育障碍提供了分子诊断。
