SETBP1 单倍体不足障碍 (SETBP1-HD) 的特点是轻度至中度智力障碍、言语和语言障碍、轻度运动发育迟缓、行为问题、肌张力减退、轻度面部畸形和视力障碍。尽管 SETBP1 突变与神经发育障碍之间存在明确的联系，但 SETBP1 在神经发育中的确切作用仍然难以捉摸。我们研究了三个 SETBP1 遗传变异的功能影响，包括两个致病突变 p.Glu545Ter 和 SETBP1 p.Tyr1066Ter，导致 SKI 和/或 SET 结构域的去除，以及 SET 结构域中的点突变 p.Thr1387Met。引入了遗传变异诱导多能干细胞（iPSC），随后分化为神经元以模拟疾病。我们测量了细胞分化、SETBP1 蛋白定位和基因表达变化的变化。数据表明 WNT 通路、RNA 聚合酶 II 通路发生变化，并确定 GATA2 是疾病扰动中的中心转录因子。此外，遗传变异改变了与神经前脑发育相关的基因组的表达，与 SETBP1-HD 表型的典型特征相匹配。该研究调查了 iPSC 分化为神经祖细胞作为 SETBP1 HD 疾病人类模型时细胞功能的变化。未来的研究可能会提供与疾病相关的进一步神经细胞规范的更多信息，以衍生成熟神经元、神经前脑细胞或脑类器官。我们开发了人类 SETBP1-HD 模型，并确定了对 WNT 和 POL2RA 通路（受 GATA2 调节的基因）的扰动。引人注目的是，SETBP1 截短突变和单核苷酸变异的神经细胞都显示出类似 SETBP1-HD 的表型。© 2024。Crown。

SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain.Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes.The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype.The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids.We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.© 2024. Crown.