Zafarullah Marwa, Tassone Flora
Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Sacramento, 95817 CA, USA.
MIND Institute, University of California Davis Medical Center, Sacramento, 95817 CA, USA.
Brain Sci. 2019 Apr 27;9(5):96. doi: 10.3390/brainsci9050096.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5' untranslated region (UTR) of the fragile X mental retardation 1 () gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.
脆性X综合征（FXS）是最常见的遗传性智力残疾（ID）形式，也是自闭症谱系障碍（ASD）已知的单基因病因。它是一种三核苷酸重复疾病，其中脆性X智力低下1（FMR1）基因5'非翻译区（UTR）中超过200个CGG重复序列会导致启动子甲基化，进而使该基因沉默，最终导致编码的脆性X智力低下1蛋白FMRP缺失。FMRP是一种RNA结合蛋白，主要作为各种mRNA翻译的抑制因子发挥作用，其中许多mRNA参与神经元突触功能和可塑性的维持与发育。除智力残疾外，FXS患者还面临多种行为挑战，包括焦虑、多动、癫痫、重复行为以及执行和语言能力方面的问题。目前，尚无治愈方法或获批药物可治疗FXS的根本病因，但在过去几年中，我们对因FMRP缺失而失调的蛋白质和信号通路的了解有所增加，这促使了临床试验的开展以及开发用于识别潜在治疗靶点的分子生物标志物的进程。在本文中，我们综述了在FXS小鼠动物模型的临床前研究中已鉴定出的候选分子生物标志物，这些标志物目前正在进行人体应用验证或已进入临床试验阶段。
