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

TitleCis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation.
Publication TypeJournal Article
Year of Publication2014
AuthorsGerhardt J, Zaninovic N, Zhan Q, Madireddy A, Nolin SL, Ersalesi N, Yan Z, Rosenwaks Z, Schildkraut CL
JournalJ Cell Biol
Date Published2014 Sep 01
KeywordsAnimals, Base Sequence, Cells, Cultured, DNA Methylation, DNA Replication, Embryonic Stem Cells, Female, Fibroblasts, Fragile X Syndrome, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Polymorphism, Single Nucleotide, Replication Origin, Trinucleotide Repeat Expansion

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 single-nucleotide 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.

Alternate JournalJ. Cell Biol.
PubMed ID25179629
PubMed Central IDPMC4151148
Grant ListP30 HD071593 / HD / NICHD NIH HHS / United States
R01 GM045751 / GM / NIGMS NIH HHS / United States
5R01-GM045751 / GM / NIGMS NIH HHS / United States