Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY
Nicole C Shaw, Kevin Chen, Kathryn O Farley, Mitchell Hedges, Catherine Forbes, Gareth Baynam, Timo Lassmann, Vanessa S Fear
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

利用诱导多能干细胞和神经疾病模型确定 SETBP1 单倍异位症分子通路,以改进对患者的诊断。
背景介绍SETBP1 单倍体缺乏症(SETBP1-HD)的特征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、肌张力低下、轻度面部畸形和视力障碍。尽管 SETBP1 基因突变与神经发育障碍之间存在着明确的联系,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 基因变异的功能影响,包括两个致病突变 p.Glu545Ter 和 SETBP1 p.Tyr1066Ter(导致 SKI 和/或 SET 结构域被移除),以及 SET 结构域中的一个点突变 p.Thr1387Met:将基因变异引入诱导多能干细胞(iPSCs),随后分化成神经元,以模拟该疾病。我们测量了细胞分化、SETBP1 蛋白定位和基因表达的变化:结果:数据表明,WNT通路、RNA聚合酶II通路发生了变化,并确定GATA2是疾病扰动的核心转录因子。此外,基因变异还改变了与神经前脑发育相关的基因组的表达,这与 SETBP1-HD 表型的典型特征相吻合:该研究调查了作为 SETBP1 HD 疾病人类模型的 iPSC 向神经祖细胞分化过程中细胞功能的变化。未来的研究可能会提供更多与神经细胞进一步分化有关的疾病信息,以衍生出成熟的神经元、神经前脑细胞或脑器官组织:我们建立了人类 SETBP1-HD 模型,并确定了受 GATA2 调控的基因 WNT 和 POL2RA 通路的干扰。令人震惊的是,SETBP1截断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。
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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
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