GGGGCC hexanucleotide repeat expansions in neurodegenerative disease

描述（由申请人提供）：过去几年对了解额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）的遗传学研究非常令人兴奋，这两种疾病密切相关，具有重叠的临床，遗传和神经病理学特征。在2011年，我们鉴定了C9 ORF 72的非编码区中的GGGGCC六核苷酸重复扩增作为与染色体9 p相关的FTD和ALS的长期寻找的原因，进一步证明了这些疾病之间的临床和分子重叠。遗传学研究现在表明，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家族。这种突变也解释了1-5%的散发患者的疾病。是什么决定了突变携带者是否会发展为FTD和/或ALS，以及症状是否早在30岁或70岁以后就出现，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，这表明可能存在毒性RNA功能获得性疾病机制。我们的工作假设是，GGGGCC重复扩增导致FTD和/或ALS，至少部分是通过异常基因表达和可变剪接变化，可能是由于这些有毒RNA灶的形成。该资助提案的具体目的集中在1）表征C9 ORF 72突变携带者的血液、脑组织和人细胞中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C9 ORF 72中GGGGCC重复序列扩增的患者的疾病发作和/或表现的遗传修饰剂; 3）研究人类基因组中其他GGGGCC重复序列对FTD和ALS发生的贡献，4）在人脑组织中使用高通量RNA测序鉴定GGGGCC重复序列扩增导致的基因表达和可变剪接变化。 拟定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学变异性的因素，并能够识别与FTD和ALS发病机制相关的mRNA靶点。 公共卫生相关性：该提案的重点是研究C9 ORF 72中GGGGCC重复扩增，这是FTD和ALS的一种新的常见遗传原因。拟定的研究旨在更好地了解导致GGGGCC重复序列携带者中观察到的可变临床和病理表型的因素，并能够识别与FTD和ALS疾病相关的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. PUBLIC HEALTH RELEVANCE: This proposal is focused on the study of GGGGCC repeat expansions in C9ORF72, a novel common genetic cause of FTD and ALS. The proposed studies aim to provide a better understanding of the factors that contribute to the variable clinicl and pathological phenotypes seen in GGGGCC repeat carriers and have the ability to lead to the identification of mRNA targets implicated in FTD and ALS disease.