PDF(Pubmed)
Abstract：
Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease-gene carrier\'s life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs.
摘要：
重复扩增障碍(REDs)是由重复DNA序列扩增超过致病阈值引起的单基因疾病。REDs的共同特征是强烈的基因型-表型相关性，其中发病年龄（AAO）和疾病进展的主要决定因素是遗传重复序列的长度。在疾病基因携带者的一生中，重复的长度可以在体细胞中扩展，通过假设驱动疾病进展的体细胞扩张过程。尽管是单基因的，个体RED是表型可变的，探索是什么遗传修饰因素驱动了这种表型变异，阐明了这组疾病常见的关键致病机制。疾病表型受发现扩增的同源基因的影响，重复序列在编码区或非编码区中的位置以及重复序列中断的存在。人类基因数据,小鼠模型和体外模型通过重复序列的体细胞突变机制涉及DNA修复途径的疾病修饰作用。因此，在扩展重复的背景下发展对这些途径的理解可能导致未来的REDs疾病改善疗法。
