Role of POU4F1 in a Novel Form of Ataxia

项目摘要/摘要 我们小组最近报道了POU4F1杂合性致病变异导致一种新的共济失调 综合症(Webb等人，2021年)。这种神经障碍的特征是儿童时期起病的共济失调，意向 震颤、低眼压和受影响的个体有轻度受损的全球发育迟缓 智力发育和言语迟缓或学习困难。POU4F1，也称为Brn3a，编码一个 包含转录因子的第IV类POU结构域，在发育中的脑和成人脑中表达。小才是 已知POU4F1在人类神经发生、神经元分化和神经元存活中的作用 神经元。因此，我们建议使用IPSC来生成人脑的细胞模型来询问 POU4F1单倍体不足的后果。我们在这项建议中的具体目标是1)确定 POU4F1的转录特征、表观遗传状态和功能异常 IPSC来源神经元的单倍体功能不全；2)评估POU4F1单倍体功能不全对IPSC的影响 使用皮质器官建立大脑发育模型；以及3)为POU4F1相关患者创建患者登记簿 共济失调和更好地定义这一新发现的疾病的临床特征。总而言之，这些研究将 揭示POU4F1相关性共济失调的病理生理、发病机制和临床病谱 并解决了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.