Role of POU4F1 in a Novel Form of Ataxia

点击翻译按钮获取中文摘要

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.