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

RFC1 中 AAGGG 重复扩展与迟发性共济失调和感觉神经病相关：从遗传原因到定义功能机制

• 批准号: MR/T001712/1
• 负责人: Andrea Cortese
• 金额: $ 165.94万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT001712%2F1
• 关键词: AAGGG; repeat; expansion; RFC1; associated

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.

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，但也可由影响大纤维感觉神经元（感觉神经病变）或前庭系统的疾病引起。当合并时，这种更严重的晚发性共济失调被称为小脑性共济失调，神经病变，前庭反射综合征（CANVAS）。我们发现复制因子C亚基1 （RFC1）中的双等位内含子AAGGG重复扩增是CANVAS和晚发性共济失调的常见原因。AAGGG重复扩增不会导致RFC1功能的明显丧失，考虑到该疾病的隐性遗传模式，这是出乎意料的，这表明可能涉及新的致病机制。本项目的主要目的是研究RFC1中存在双等位基因AAGGG扩增时神经退行性变的分子机制。我们将利用体外实验、果蝇模型以及患者来源的细胞系和组织的优势，采用综合方法来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RFC1亚型、非编码转录本、邻近和远端基因和/或重组3D染色质结构的非常规功能丧失的存在。

项目成果

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

SORD 的双等位基因突变会导致一种常见且可治疗的遗传性神经病，对糖尿病有影响

• DOI: 10.1038/s41588-020-0615-4
• 发表时间: 2020-05
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Cortese A;Zhu Y;Rebelo AP;Negri S;Courel S;Abreu L;Bacon CJ;Bai Y;Bis-Brewer DM;Bugiardini E;Buglo E;Danzi MC;Feely SME;Athanasiou-Fragkouli A;Haridy NA;Inherited Neuropathy Consortium;Isasi R;Khan A;Laurà M;Magri S;Pipis M;Pisciotta C;Powell E;Rossor AM;Saveri P;Sowden JE;Tozza S;Vandrovcova J;Dallman J;Grignani E;Marchioni E;Scherer SS;Tang B;Lin Z;Al-Ajmi A;Schüle R;Synofzik M;Maisonobe T;Stojkovic T;Auer-Grumbach M;Abdelhamed MA;Hamed SA;Zhang R;Manganelli F;Santoro L;Taroni F;Pareyson D;Houlden H;Herrmann DN;Reilly MM;Shy ME;Zhai RG;Zuchner S
• 通讯作者: Zuchner S

Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis.

• DOI: 10.1016/j.jns.2021.118061
• 发表时间: 2021-11-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Abramzon, Yevgenya;Dewan, Ramita;Cortese, Andrea;Resnick, Susan;Ferrucci, Luigi;Houlden, Henry;Traynor, Bryan J.
• 通讯作者: Traynor, Bryan J.

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

• DOI: 10.1111/ene.15310
• 发表时间: 2022-03-23
• 期刊: EUROPEAN JOURNAL OF NEUROLOGY
• 影响因子: 5.1
• 作者: Beijer, Danique;Dohrn, Maike F.;Baets, Jonathan
• 通讯作者: Baets, Jonathan