Mor-Shaked Hagar, Eiges Rachel
Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
Genes (Basel). 2016 Sep 28;7(10):77. doi: 10.3390/genes7100077.
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a loss-of-function mutation by a CGG repeat expansion at the 5' untranslated region of the X-linked gene. Expansion of the CGG repeats beyond 200 copies results in protein deficiency by leading to aberrant methylation of the promoter and the switch from active to repressive histone modifications. Additionally, the CGGs become increasingly unstable, resulting in high degree of variation in expansion size between and within tissues of affected individuals. It is still unclear how the FMR1 protein (FMRP) deficiency leads to disease pathology in neurons. Nor do we know the mechanisms by which the CGG expansion results in aberrant DNA methylation, or becomes unstable in somatic cells of patients, at least in part due to the lack of appropriate animal or cellular models. This review summarizes the current contribution of pluripotent stem cells, mutant human embryonic stem cells, and patient-derived induced pluripotent stem cells to disease modeling of FXS for basic and applied research, including the development of new therapeutic approaches.
脆性X综合征（FXS）是最常见的遗传性认知障碍形式。它是由位于X连锁基因5'非翻译区的CGG重复序列扩增导致的功能丧失突变引起的。CGG重复序列扩增超过200个拷贝会导致启动子异常甲基化，以及从活性组蛋白修饰转变为抑制性组蛋白修饰，从而导致蛋白质缺乏。此外，CGG变得越来越不稳定，导致受影响个体的组织之间和组织内部的扩增大小存在高度差异。目前尚不清楚FMR1蛋白（FMRP）缺乏如何导致神经元疾病病理。我们也不知道CGG扩增导致异常DNA甲基化或在患者体细胞中变得不稳定的机制，至少部分原因是缺乏合适的动物或细胞模型。这篇综述总结了多能干细胞、突变人类胚胎干细胞和患者来源的诱导多能干细胞目前对FXS疾病建模在基础和应用研究方面的贡献，包括新治疗方法的开发。
