Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation

Jeannine Gerhardt, Nikica Zaninovic, Qiansheng Zhan, Advaitha Madireddy, Sarah L. Nolin, Nicole Ersalesi, Zi Yan, Zev Rosenwaks, Carl L. Schildkraut

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a singlenucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.

Original languageEnglish (US)
Pages (from-to)599-607
Number of pages9
JournalJournal of Cell Biology
Issue number5
StatePublished - 2014

ASJC Scopus subject areas

  • Cell Biology


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