GGGGCC hexanucleotide repeat expansions in neurodegenerative disease

描述（由申请人提供）：在过去的几年里，对额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）这两种密切相关的破坏性神经退行性疾病的遗传学研究取得了令人兴奋的进展，这两种疾病具有重叠的临床、遗传和神经病理学特征。2011年，我们在C9ORF72的非编码区发现了GGGGCC六核苷酸重复扩增，这是长期寻找的与9p染色体相关的FTD和ALS的原因，进一步证明了这些疾病之间的临床和分子重叠。遗传研究现在表明，这种重复扩增是家族性FTD和ALS的最常见原因，解释了全球10-20%的FTD和25-40%的ALS家庭。这种突变也解释了1-5%散发患者的疾病。是什么决定了突变携带者是否会患上FTD和/或ALS，以及症状是早在30岁还是70岁以后出现，目前还没有研究。有趣的是，与其他非编码重复扩增疾病的研究一致，我们发现重复扩增导致核RNA灶的形成，这可能是一种毒性RNA功能获得的疾病机制。我们的工作假设是，GGGGCC重复扩增导致FTD和/或ALS，至少部分是通过这些有毒RNA灶形成的异常基因表达和选择性剪接变化引起的。该资助提案的具体目标是：1)研究C9ORF72突变携带者血液、脑组织和人类细胞中GGGGCC重复序列大小的变异性，并详细研究重复序列大小对临床和病理表型的影响；2)鉴定携带GGGGCC重复扩增的C9ORF72患者疾病发病和/或表现的遗传修饰因子；3)研究人类基因组中其他GGGGCC重复序列对FTD和ALS发展的贡献；4)利用高通量RNA测序技术鉴定人脑组织中GGGGCC重复序列扩增引起的基因表达和选择性剪接变化。拟议的研究有助于更好地了解与GGGGCC重复扩增相关的临床和病理变异的因素，并有能力鉴定与FTD和ALS发病机制有关的mRNA靶点。

DESCRIPTION (provided by applicant): The last few years have been extremely exciting for genetic research into the understanding of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two closely related devastating neurodegenerative disorders with overlapping clinical, genetic and neuropathologic features. In 2011, we identified a GGGGCC hexanucleotide repeat expansion in the non-coding region of C9ORF72 as the long- sought cause of FTD and ALS linked to chromosome 9p, further demonstrating the clinical and molecular overlap between these diseases. Genetic studies now suggest that this repeat expansion is the most common cause of familial FTD and ALS, explaining 10-20% of FTD and 25-40% of ALS families worldwide. This mutation also explains the disease in 1-5% of sporadic patients. What determines whether mutation carriers develop FTD and/or ALS and whether symptoms occur as early as 30 years of age or after the age of 70 has not yet been studied. Interestingly, in line with studies in other non-coding repeat expansion disorders, we showed that the repeat expansion leads to the formation of nuclear RNA foci, suggesting a possible toxic RNA gain-of-function disease mechanism. Our working hypothesis is that GGGGCC repeat expansions cause FTD and/or ALS, at least in part, through aberrant gene expression and alternative splicing changes that may result from the formation of these toxic RNA foci. The Specific Aims of this grant proposal are focused on 1) characterization of the variability in GGGGCC repeat size in blood, brain tissue and human cells in C9ORF72 mutation carriers and a detailed study of the effect of repeat size on clinical and pathological phenotypes; 2) identification of genetic modifiers of disease onset and/or presentation in patients carrying GGGGCC repeat expansions in C9ORF72; 3) study of the contribution of other GGGGCC repeats in the human genome to the development of FTD and ALS and 4) identification of gene expression and alternative splicing changes resulting from GGGGCC repeat expansions using high-throughput RNA sequencing in human brain tissue. The proposed studies are relevant to obtain a better understanding of the factors that contribute to the clinical and pathological variability associated with GGGGCC repeat expansions and have the ability to lead to the identification of mRNA targets implicated in FTD and ALS pathogenesis.