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CGG-repeat instability in Fragile X syndrome patient-derived stem cells

Friday, September 18, 2015 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • Yifan Zhou
  • Daman Kumari
  • Bruce Hayward
  • Karen Usdin


Fragile X syndrome (FXS) is caused by expansion of a CGG-repeat tract in the 5’ UTR of the fragile X mental retardation (FMR1) gene that results in repeat-mediated FMR1 gene silencing. The lack of a good tissue culture model has hampered efforts to understand the expansion mechanism and the mechanism of gene silencing. Work in affected humans and in mouse models has suggested that expansion may occur during oogenesis or early stages of embryogenesis and that silencing occurs during embryonic development. The purpose of this study was to establish a human cell culture model for studying repeat expansion. The stability of the repeat was examined in patient-derived iPSCs and in neural progenitors and neurons derived from these iPSCs and in individual clones isolated from a FXS hESC line. No expansions were seen in the iPSCs, however, a small expansion was observed upon their initial differentiation into neuronal cells. Expansions were also not seen in clones derived from FXS hESCs. This may indicate that expansions occur prezygotically, consistent with observations from FX mouse model. In contrast, contractions were seen in both ESCs and iPSCs. Similar contractions in the early human embryo may contribute to the frequent mosaicism for different repeat lengths that are seen in humans with FXS. Furthermore, hESCs clones that were mosaic for methylated and unmethylated alleles, a selective growth advantage was observed for the methylated allele. This may have important implications for our understanding of the silencing process the disease pathology seen in individuals with large, unsilenced alleles.

Category: Genetics and Genomics