The AAGGG repeat expansion in RFC1 associated with late-onset ataxia and sensory neuropathy: from genetic cause to defining the functional mechanism

迟发性共济失调是神经科会诊的常见原因，但其病因往往是特发性的。共济失调主要由小脑功能障碍引起，但也可能由影响大纤维感觉神经元（感觉神经元病）或前庭系统的疾病引起。当联合使用时，这种更严重的迟发性共济失调被称为小脑共济失调、神经病、前庭反射消失综合征（CANVAS）。我们确定了复制因子C亚基1（RFC 1）中的双等位基因内含子AAGGG重复扩增是CANVAS和迟发性共济失调的常见原因。AAGGG重复扩增不会导致RFC 1功能的明显丧失，这是出乎意料的，因为该疾病的隐性遗传模式，并表明可能涉及新的致病机制。该项目的主要目的是研究RFC 1中存在双等位基因AAGGG扩增的神经变性的分子机制。我们将通过利用体外实验、果蝇模型以及患者来源的细胞系和组织来使用组合方法，以测试由转录的内含子重复序列编码的毒性五肽重复蛋白的剂量依赖性功能获得和/或组织特异性RFC 1同种型、非编码转录物、邻近和远距离基因和/或重组3D染色质结构。

Late-onset ataxia is a common reason for neurological consultation, but its cause often remains idiopathic. Ataxia primarily results from cerebellar dysfunction but can also be caused by disorders affecting the large-fibre sensory neurons (sensory neuronopathy) or the vestibular system. When in combination, this more severe late onset ataxia is termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We identified a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) as a common cause of CANVAS and late-onset ataxia. The AAGGG repeat expansion does not lead to overt loss of function of RFC1, which is unexpected given the recessive pattern of inheritance of the disease and suggests that novel disease-causing mechanisms could be involved. The main objective of this project is to investigate the molecular mechanisms underlying neurodegeneration in the presence of biallelic AAGGG expansions in RFC1. We will use a combined approach by taking advantage of in vitro experiments, Drosophila model as well as patients'-derived cell lines and tissues in order to test the presence of a dose-dependent gain-of-function of toxic pentapeptide repeat proteins encoded by the transcribed intronic repeated sequence and/or unconventional loss-of-function of tissue specific RFC1 isoforms, non-coding transcripts, neighboring and distant genes and/or reorganization 3D chromatin structure.