Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability.

1 型神经纤维瘤病 (NF1) 是一种常见的神经发育障碍，由一系列不同的生殖系NF1基因突变引起，传统上被视为等效的功能丧失等位基因。为了专门解决具有相当大临床异质性的疾病中的突变等效性问题，我们设计了七种同基因人类诱导多能干细胞系，每一种都具有不同的 NF1 患者NF1突变，以确定NF1突变对人类中枢神经系统细胞的潜在差异影响和组织。尽管所有突变都增加了二维神经祖细胞 (NPC) 和星形胶质细胞的增殖和 RAS 活性，但我们观察到NF1之间的显着差异2D NPC 多巴胺水平的突变，以及 3D NPC 增殖、凋亡和发育中的大脑类器官的神经元分化。总之，这些发现证明了NF1基因突变在细胞和组织水平上的不同影响，表明生殖系NF1基因突变是临床变异性的一个因素。