Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

The unique genetic, epigenetic, and cellular alterations involved in the pathogenesis of fragile X syndrome (FXS) present a significant challenge for the modeling of this disorder. Although animal models have been useful in the study of FXS, their failure to recapitulate the CGG expansion-mediated silencing of the FMR1 gene prompted the development of human based in vitro modeling systems. The establishment of human pluripotent stem cell (PSC) models for FXS furnished new possibilities for the study of the disorder, by providing an unlimited source of disease-relevant cell types carrying the genetic profile associated with FXS. The differential use of embryonic stem cell and induced PSC models of FXS have led to novel insights regarding the epigenetic silencing of the FMR1 gene, the neural defects associated with the disorder, and the mechanism involved in CGG repeat instability. These studies confirmed the immense value of FXS PSCs in the investigation of mechanisms underlying disease manifestations and highlighted their potential in the development of targeted therapy.