Hansen Nicole, Dischler Anna, Dias Caroline
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Int J Mol Sci. 2024 Dec 30;26(1):214. doi: 10.3390/ijms26010214.
(Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The most well-known of these is Fragile X syndrome, a neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, and seizures. However, CGG expansions of different sizes also confer a risk of neuropsychiatric and neurodegenerative disorders throughout the lifespan, through distinct molecular mechanisms. Although Fragile X syndrome is associated with downstream synaptic deficits and neuronal hyperexcitability, work in the past decade has demonstrated that both the causative trinucleotide repeat expansion and FMRP itself play important roles in nuclear function and regulation, including non-canonical nucleic acid structure formation and chromatin dynamics. These effects are critical to cellular pathophysiology, although the full extent of their contribution to clinical phenotypes is only just emerging. Here, we present a focused review on some of the nuclear consequences of /FMRP dysregulation, including parallels in other repeat expansion disorders, ranging from studies in model systems to human cells and tissues.
脆性X信使核糖核蛋白1（Fragile X messenger ribonucleoprotein 1）位于X染色体上，编码多功能FMR1蛋白（FMRP），该蛋白对大脑发育和功能至关重要。此位点的三核苷酸CGG重复扩增会导致一系列神经疾病，统称为脆性X相关病症。其中最广为人知的是脆性X综合征，这是一种神经发育障碍，与综合征性面部特征、自闭症、智力残疾和癫痫有关。然而，不同大小的CGG扩增也会在整个生命周期中通过不同的分子机制带来神经精神疾病和神经退行性疾病的风险。尽管脆性X综合征与下游突触缺陷和神经元过度兴奋有关，但过去十年的研究表明，致病性三核苷酸重复扩增和FMRP本身在核功能和调控中都发挥着重要作用，包括非经典核酸结构形成和染色质动力学。这些作用对细胞病理生理学至关重要，尽管它们对临床表型贡献的全部程度才刚刚显现出来。在此，我们重点综述FMRP失调的一些核后果，包括与其他重复扩增疾病的相似之处，范围从模型系统研究到人类细胞和组织。
