Abstract
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand beyond 200 copies, they lead to epigenetic gene silencing of the gene. In addition, the greater the allele size, the more likely it will become unstable and exhibit mosaicism for expansion size between and within tissues in affected individuals. The timing and mechanisms of FMR1 epigenetic gene silencing and repeat instability are far from being understood given the lack of appropriate cellular and animal models that can fully recapitulate the molecular features characteristic of the disease pathogenesis in humans. This review summarizes the data collected to date from mutant human embryonic stem cells, induced pluripotent stem cells, and hybrid fusions, and discusses their contribution to the investigation of FXS, their key limitations, and future prospects.
Highlights
Fragile X syndrome (FXS; OMIM#300624) is the most common heritable form of cognitive impairment (1 in 4000 male and 1 in 8000 female births)
PM alleles confer a risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), both of which are thought to result from a combination of toxic gain-of-function RNA and repeat-associated non-ATG
When CGGs increase in size and reach the FM range, it results in aberrant DNA methylation in a region that initiates approximately 650-850 nucleotides upstream to the CGGs and extends into intron 1 of the FMR1 gene [47,65,66]
Summary
Fragile X syndrome (FXS; OMIM#300624) is the most common heritable form of cognitive impairment (1 in 4000 male and 1 in 8000 female births). This review summarizes the data collected to date on the contributions of currently available PSC model systems to investigate the timing and mechanisms governing epigenetics and repeat instability in FXS, their apparent limitations, and future prospects. The contribution of these cell models to a better understanding of the neural phenotype of the disease, including the effect of RNA/protein toxicity by gain-of-function mechanisms contributed by unmethylated FM alleles, and their therapeutic potential is beyond the scope of this manuscript and can be found elsewhere [40,41,42]. Induced pluripotent cells (iPSCs) derived from patients’ somatic cells by over-expression of a defined set of transcription factors
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