Role of POU4F1 in a Novel Form of Ataxia

项目总结/摘要 我们的研究小组最近报道POU 4F 1的杂合致病性变体可引起一种新的共济失调 综合征（Webb等，2021年）。这种神经系统疾病的特点是儿童发病共济失调，意图 震颤和肌张力减退，受影响的个体具有整体发育迟缓， 智力发育和语言迟缓或学习困难。POU 4F 1，也称为BRN 3A，编码一种 IV类POU结构域包含在发育和成人脑中表达的转录因子。之甚少 已知POU 4F 1在人类神经发生、神经元分化和神经元存活中发挥的作用 神经元因此，我们建议使用iPSC来生成人脑的细胞模型，以询问 POU 4F 1单倍不足的后果。我们在本提案中的具体目标是：1）确定 POU 4F 1导致的转录特征、表观遗传状态和功能异常 2）评估P0 U4 F1单倍不足在iPSC衍生的神经元中的影响; 使用皮质类器官的发育中的大脑模型;以及3）创建POU 4F 1相关的患者登记处。 共济失调和更好地定义这种新发现的疾病的临床特征。这些研究将 揭示POU 4F 1相关共济失调的病理生理学、疾病机制和疾病的临床谱 并解决人类神经发育生物学的基本问题。

PROJECT SUMMARY/ABSTRACT Heterozygous, pathogenic variants in POU4F1 were recently reported by our group to cause a novel ataxia syndrome (Webb et al., 2021). This neurological disorder is characterized by childhood onset ataxia, intention tremor, and hypotonia, and affected individuals have global developmental delay with mildly impaired intellectual development and speech delay or learning difficulties. POU4F1, also known as BRN3A, encodes a class IV POU-domain containing transcription factor expressed in the developing and adult brain. Little is known about the role POU4F1 plays in neurogenesis, neuronal differentiation, and neuronal survival in human neurons. Therefore, we propose to use iPSC to generate cellular models of the human brain to interrogate the consequences of POU4F1 haploinsufficiency. Our specific aims in this proposal are to 1) determine transcriptional signatures, epigenetic status, and functional abnormalities resulting from POU4F1 haploinsufficiency in iPSC – derived neurons; 2) assess the impact of POU4F1 haploinsufficiency in a iPSC model of the developing brain using cortical organoids; and 3) create a patient registry for POU4F1-related ataxia and better define the clinical features of this newly identified disorder. Taken together, these studies will uncover the pathophysiology, disease mechanism, and clinical spectrum of disease of POU4F1-related ataxia and address fundamental questions of human neurodevelopmental biology.