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Is Friedreich ataxia an epigenetic disorder?

机译：Friedreich共济失调是一种表观遗传疾病吗？

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Friedreich ataxia (FRDA) is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases, in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA?TTC and the tandem array is located in the first intron of the frataxin ( FXN ) gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures that have the potential to affect gene expression in a number of ways. For example, triplex formation in vitro and in bacteria leads to the formation of persistent RNA:DNA hybrids that block transcription. In addition, these repeats have been shown to affect splicing in model systems. More recently, it has been shown that the region flanking the repeats in the FXN gene is enriched for epigenetic marks characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against different models for the repeat-mediated mRNA deficit.
机译：Friedreich共济失调（FRDA）是一种隐性遗传的令人衰弱且经常致命的神经系统疾病。它属于被称为重复扩增疾病的遗传疾病，其中病理学是由重复序列超过关键阈值的串联重复序列的遗传所带来的有害后果引起的。就FRDA而言，重复单元是三联体GAA？TTC，串联阵列位于frataxin（FXN）基因的第一个内含子中。出现病理是因为扩展的等位基因使FXN成熟mRNA的水平低于正常水平，从而降低了FXN基因产物frataxin的水平。这些重复序列会形成各种异常的DNA结构，这些结构可能以多种方式影响基因表达。例如，体外和细菌中三链体的形成导致形成持久性RNA：DNA杂合体，从而阻止转录。此外，这些重复已显示出会影响模型系统中的剪接。最近，已经表明，FXN基因的重复序列侧翼的区域富集了基因组转录抑制区域特征性的表观遗传标记。然而，内含子的重复到底如何导致FRDA中的FXN mRNA缺乏一直是许多争论的主题。查明造成FRDA中FXN mRNA缺陷的一种或多种机制对于开发这种目前无法治愈的疾病的治疗方法很重要。这篇评论讨论了支持和反对重复介导的mRNA缺陷的不同模型的证据。

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