Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells.
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-linkedfragile X mental retardation 1 (FMR1)gene. Expansion of the CGG repeats beyond 200 copies results in protein deficiency by leading to aberrant methylation of theFMR1promoter 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.
Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel. hagar.mor@mail.huji.ac.il.
Hagar
H
Mor-Shaked
Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel. rachela@szmc.org.il.
Rachel
R
Eiges
FMR1 gene; FMRP; disease modeling; epigenetics; fragile X syndrome; human embryonic stem cells; neurodevelopment; patient-derived iPS cells; repeat somatic instability
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